A new population pharmacokinetic model for recombinant factor IX-Fc fusion concentrate including young children with haemophilia B.

AIMS: Recombinant factor IX Fc fusion protein (rFIX-Fc) is an extended half-life factor concentrate administered to haemophilia B patients. So far, a population pharmacokinetic (PK) model has only been published for patients aged ≥12 years. The aim was to externally evaluate the predictive performance of the published rFIX-Fc population PK model for patients of all ages and develop a model that describes rFIX-Fc PK using real-world data. METHODS: We collected prospective and retrospective data from patients with haemophilia B treated with rFIX-Fc and included in the OPTI-CLOT TARGET study (NTR7523) or United Kindom (UK)-EHL Outcomes Registry (NCT02938156). Predictive performance was assessed by comparing predicted with observed FIX activity levels. A new population PK model was constructed using nonlinear mixed-effects modelling. RESULTS: Real-world data were obtained from 37 patients (median age: 16 years, range 2-71) of whom 14 were aged <12 years. Observed FIX activity levels were significantly higher than levels predicted using the published model, with a median prediction error of -48.8%. The new model showed a lower median prediction error (3.4%) and better described rFIX-Fc PK, especially for children aged <12 years. In the new model, an increase in age was correlated with a decrease in clearance (P < .01). CONCLUSIONS: The published population PK model significantly underpredicted FIX activity levels. The new model better describes rFIX-Fc PK, especially for children aged <12 years. This study underlines the necessity to strive for representative population PK models, thereby avoiding extrapolation outside the studied population.

Genome-wide association study of milk production traits in a crossbred dairy sheep population using three statistical models.

Milk production is one of the most important characteristics of dairy sheep, and the identification of genes affecting milk production traits is critical to understanding the genetics and improve milk production in future generations. Three statistical techniques, namely GWAS, ridge-regression BLUP and BayesC π , were used to identify SNPs in significant association with three milk production traits (milk yield, fat yield and protein yield) in a crossbred dairy sheep population. The results suggested that chromosomes 1, 3, 4, 5, 7 and 11 were likely to harbor genes important to milk production because these chromosomes had the greatest top-100-SNP variance contributions on the three milk production traits. The GWAS analysis identified between 74 and 288 genome-wide significant SNP (P < 0.05) whereas the BayesCπ model revealed between six and 63 SNPs, each with >95% posterior probability of inclusion as having a non-zero association effect on at least one of the three milk production traits. Positional candidate genes for milk production in sheep were searched, based on the sheep genomic assembly OAR version 3.1, such as those which map position coincided with or was located within 0.1 Mbp of a genome-wide suggestive or significant SNP. These identified SNPs and candidate genes supported some previous findings and also added new information about genetic markers for genetic improvement of lactation in dairy sheep, but keeping in mind that the majority of these positional candidate genes are not necessarily true causative loci for these traits and future validations are thus necessary.

Estimation of genomic breed composition of individual animals in composite beef cattle.

Three statistical models (an admixture model, linear regression, and ridge-regression BLUP) and two strategies for selecting SNP panels (uniformly spaced vs. maximum Euclidean distance of SNP allele frequencies between ancestral breeds) were compared for estimating genomic-estimated breed composition (GBC) in Brangus and Santa Gertrudis cattle, respectively. Animals were genotyped with a GeneSeek Genomic Profiler bovine low-density version 4 SNP chip. The estimated GBC was consistent among the uniformly spaced SNP panels, and values were similar between the three models. However, estimated GBC varied considerably between the three methods when using fewer than 10 000 SNPs that maximized the Euclidean distance of allele frequencies between the ancestral breeds. The admixture model performed most consistently across various SNP panel sizes. For the other two models, stabilized estimates were obtained with an SNP panel size of 20 000 SNPs or more. Based on the uniformly spaced 20K SNP panel, the estimated GBC was 69.8-70.5% Angus and 29.5-30.2% Brahman for Brangus, and 63.9-65.3% Shorthorn and 34.7-36.1% Brahman in Santa Gertrudis. The estimated GBC of ancestries for Santa Gertrudis roughly agreed with the pedigree-expected values. However, the estimated GBC in Brangus showed a considerably larger Angus composition than the pedigree-expected value (62.5%). The elevated Angus composition in the Brangus could be due to the mixture of some 1/2 Ultrablack animals (Brangus × Angus). Another reason could be the consequences of selection in Brangus cattle for phenotypes where the Angus breed has advantages.

A unified local objective function for optimally selecting SNPs on arrays for agricultural genomics applications.

Over the years, ad-hoc procedures were used for designing SNP arrays, but the procedures and strategies varied considerably case by case. Recently, a multiple-objective, local optimization (MOLO) algorithm was proposed to select SNPs for SNP arrays, which maximizes the adjusted SNP information (E score) under multiple constraints, e.g. on MAF, uniformness of SNP locations (U score), the inclusion of obligatory SNPs and the number and size of gaps. In the MOLO, each chromosome is split into equally spaced segments and local optima are selected as the SNPs having the highest adjusted E score within each segment, conditional on the presence of obligatory SNPs. The computation of the adjusted E score, however, is empirical, and it does not scale well between the uniformness of SNP locations and SNP informativeness. In addition, the MOLO objective function does not accommodate the selection of uniformly distributed SNPs. In the present study, we proposed a unified local function for optimally selecting SNPs, as an amendment to the MOLO algorithm. This new local function takes scalable weights between the uniformness and informativeness of SNPs, which allows the selection of SNPs under varied scenarios. The results showed that the weighting between the U and the E scores led to a higher imputation concordance rate than the U score or E score alone. The results from the evaluation of six commercial bovine SNP chips further confirmed this conclusion.

Rare variants in GP1BB are responsible for autosomal dominant macrothrombocytopenia.

The von Willebrand receptor complex, which is composed of the glycoproteins Ibα, Ibß, GPV, and GPIX, plays an essential role in the earliest steps in hemostasis. During the last 4 decades, it has become apparent that loss of function of any 1 of 3 of the genes encoding these glycoproteins (namely, GP1BA, GP1BB, and GP9) leads to autosomal recessive macrothrombocytopenia complicated by bleeding. A small number of variants in GP1BA have been reported to cause a milder and dominant form of macrothrombocytopenia, but only 2 tentative reports exist of such a variant in GP1BB By analyzing data from a collection of more than 1000 genome-sequenced patients with a rare bleeding and/or platelet disorder, we have identified a significant association between rare monoallelic variants in GP1BB and macrothrombocytopenia. To strengthen our findings, we sought further cases in 2 additional collections in the United Kingdom and Japan. Across 18 families exhibiting phenotypes consistent with autosomal dominant inheritance of macrothrombocytopenia, we report on 27 affected cases carrying 1 of 9 rare variants in GP1BB.

Genome-wide association study for response to vaccination in Angus calves1.

BACKGROUND: Bovine respiratory disease complex (BRDC) is one of the most important sources of loss within the beef cattle industry in the USA. Steps have been taken to reduce the incidence of BRDC through vaccination. Despite the effectiveness of vaccines, large proportions of cattle still experience morbidity and mortality. Identification of genomic regions that are associated with variation in response to vaccination would allow for the selection of individuals genetically predisposed to respond to vaccination based on specific markers, while heritability and accuracy estimates would help facilitate genomic selection. This in turn may lead to selection for beef cattle herds that may have lower incidence rate of BRDC after vaccination. This study utilizes an Angus herd of more than 2000 head of cattle to identify these regions of association. RESULTS: Genome wide association studies were performed for viral neutralization antibody level and response to vaccination traits against four different viruses associated with BRDC: bovine viral diarrhea virus 1 and 2 (BVDV1 and BVDV2), bovine respiratory syncytial virus (BRSV), and bovine herpesvirus (BHV1). A total of six 1-Mb windows were associated with greater than 1% of the genetic variance for the analyzed vaccination response traits. Heritabilities ranged from 0.08 to 0.21 and prediction accuracy ranged from 0.01 to 0.33 across 7 different vaccination traits. CONCLUSIONS: Although six 1-Mb windows were identified as associated with 1% or greater genetic variance for viral neutralization antibody level and response to vaccination traits, few genes around these windows could readily be considered candidates. This indicates the need for further functional genomic annotation, as these regions appear to be gene deserts. Traits ranged from lowly to moderately heritable, which indicated the potential for selection of individuals that are genetically pre-disposed to respond to vaccination. The relatively low amount of genetic variance accounted for by any 1-Mb window indicated that viral neutralization antibody level and response to vaccination traits are polygenic in nature. Selection for these traits is possible, but likely to be slow due to the low heritabilities and absence of markers with high genetic variation associated with them.

Nanofabrication of plasmonic structures on insulating substrates by resist-on-metal bilayer lift-off.

In last few decades, micro- and nano-fabrication techniques based on photolithography and electron beam lithography have advanced greatly, mainly in the field of semiconductor fabrication. Such techniques are generally transferrable to the fabrication of plasmonic structures and metamaterials. However, plasmonic devices often require a transparent insulating substrate to be operational at visible or near-infrared wavelengths. Here we report a resist-on-metal bilayer lift-off technique enabling the fabrication of plasmonic structures on insulating substrates. The metal layer under the resist eliminates major difficulties in lithography, such as charging during electron beam exposure and uncontrolled diffuse optical scattering during photolithography. In addition, the resist-on-metal bilayer can be migrated to different substrates with minimal process alteration, because the material properties of the substrate, such as secondary electron emission or optical reflectance, become irrelevant due to the shielding provided by the metal layer. As demonstrations, we fabricate large-scale plasmonic waveguides and Bragg gratings, adiabatically-modulated plasmonic waveguide couplers, and plasmonic nanoantenna arrays using the resist-on-metal bilayer lift-off process. The process can also be used to define structures formed of other materials such as dielectrics.

Grating couplers fabricated by e-beam lithography for long-range surface plasmon waveguides embedded in a fluoropolymer.

Long-range surface plasmon polariton waveguides consisting of Au stripes integrated with input and output grating couplers embedded in thick Cytop claddings are proposed and demonstrated experimentally. Under the right conditions, grating couplers enable broadside (top) coupling with good efficiency while producing a low level of background light. The scheme does not require high-quality input and output edge facets, and it simplifies optical alignments. We demonstrate coupling using a cleaved bow-tie fiber and a lensed fiber, and we determine the grating coupling efficiencies in both cases over a broad operating wavelength range. The lensed fiber produces a better overlap with the long-range surface plasmon mode of interest and thus results in a better coupling efficiency with essentially no background light as observed on an infrared camera. The measurements are compared with theoretical results obtained using a realistic model of the structures, including out-of-plane curvature in the grating profile resulting from our fabrication process. The coupling scheme along with the surface plasmon waveguides hold strong potential for biosensing applications.

Evaluation of genotyping concordance for commercial bovine SNP arrays using quality-assurance samples.

SNP arrays are widely used in genetic research and agricultural genomics applications, and the quality of SNP genotyping data is of paramount importance. In the present study, SNP genotyping concordance and discordance were evaluated for commercial bovine SNP arrays based on two types of quality assurance (QA) samples provided by Neogen GeneSeek. The genotyping discordance rates (GDRs) between chips were on average between 0.06% and 0.37% based on the QA type I data and between 0.05% and 0.15% based on the QA type II data. The average genotyping error rate (GER) pertaining to single SNP chips, based on the QA type II data, varied between 0.02% and 0.08% per SNP and between 0.01% and 0.06% per sample. These results indicate that genotyping concordance rate was high (i.e. from 99.63% to 99.99%). Nevertheless, mitochondrial and Y chromosome SNPs had considerably elevated GDRs and GERs compared to the SNPs on the 29 autosomes and X chromosome. The majority of genotyping errors resulted from single allotyping errors, which also included the opposite instances for allele 'dropout' (i.e. from AB to AA or BB). Simultaneous allotyping errors on both alleles (e.g. mistaking AA for BB or vice versa) were relatively rare. Finally, a list of SNPs with a GER greater than 1% is provided. Interpretation of association effects of these SNPs, for example in genome-wide association studies, needs to be taken with caution. The genotyping concordance information needs to be considered in the optimal design of future bovine SNP arrays.

Effect of Low-Dose Intracoronary Alteplase During Primary Percutaneous Coronary Intervention on Microvascular Obstruction in Patients With Acute Myocardial Infarction: A Randomized Clinical Trial.

Importance: Microvascular obstruction commonly affects patients with acute ST-segment elevation myocardial infarction (STEMI) and is associated with adverse outcomes. Objective: To determine whether a therapeutic strategy involving low-dose intracoronary fibrinolytic therapy with alteplase infused early after coronary reperfusion will reduce microvascular obstruction. Design, Setting, and Participants: Between March 17, 2016, and December 21, 2017, 440 patients presenting at 11 hospitals in the United Kingdom within 6 hours of STEMI due to a proximal-mid-vessel occlusion of a major coronary artery were randomized in a 1:1:1 dose-ranging trial design. Patient follow-up to 3 months was completed on April 12, 2018. Interventions: Participants were randomly assigned to treatment with placebo (n = 151), alteplase 10 mg (n = 144), or alteplase 20 mg (n = 145) by manual infusion over 5 to 10 minutes. The intervention was scheduled to occur early during the primary PCI procedure, after reperfusion of the infarct-related coronary artery and before stent implant. Main Outcomes and Measures: The primary outcome was the amount of microvascular obstruction (% left ventricular mass) demonstrated by contrast-enhanced cardiac magnetic resonance imaging (MRI) conducted from days 2 through 7 after enrollment. The primary comparison was the alteplase 20-mg group vs the placebo group; if not significant, the alteplase 10-mg group vs the placebo group was considered a secondary analysis. Results: Recruitment stopped on December 21, 2017, because conditional power for the primary outcome based on a prespecified analysis of the first 267 randomized participants was less than 30% in both treatment groups (futility criterion). Among the 440 patients randomized (mean age, 60.5 years; 15% women), the primary end point was achieved in 396 patients (90%), 17 (3.9%) withdrew, and all others were followed up to 3 months. In the primary analysis, the mean microvascular obstruction did not differ between the 20-mg alteplase and placebo groups (3.5% vs 2.3%; estimated difference, 1.16%; 95% CI, -0.08% to 2.41%; P = .32) nor in the analysis of 10-mg alteplase vs placebo groups (2.6% vs 2.3%; estimated difference, 0.29%; 95% CI, -0.76% to 1.35%; P = .74). Major adverse cardiac events (cardiac death, nonfatal MI, unplanned hospitalization for heart failure) occurred in 15 patients (10.1%) in the placebo group, 18 (12.9%) in the 10-mg alteplase group, and 12 (8.2%) in the 20-mg alteplase group. Conclusions and Relevance: Among patients with acute STEMI presenting within 6 hours of symptoms, adjunctive low-dose intracoronary alteplase given during the primary percutaneous intervention did not reduce microvascular obstruction. The study findings do not support this treatment. Trial Registration: ClinicalTrials.gov Identifier: NCT02257294.

Improving accuracy of genomic prediction in Brangus cattle by adding animals with imputed low-density SNP genotypes.

Reliable genomic prediction of breeding values for quantitative traits requires the availability of sufficient number of animals with genotypes and phenotypes in the training set. As of 31 October 2016, there were 3,797 Brangus animals with genotypes and phenotypes. These Brangus animals were genotyped using different commercial SNP chips. Of them, the largest group consisted of 1,535 animals genotyped by the GGP-LDV4 SNP chip. The remaining 2,262 genotypes were imputed to the SNP content of the GGP-LDV4 chip, so that the number of animals available for training the genomic prediction models was more than doubled. The present study showed that the pooling of animals with both original or imputed 40K SNP genotypes substantially increased genomic prediction accuracies on the ten traits. By supplementing imputed genotypes, the relative gains in genomic prediction accuracies on estimated breeding values (EBV) were from 12.60% to 31.27%, and the relative gain in genomic prediction accuracies on de-regressed EBV was slightly small (i.e. 0.87%-18.75%). The present study also compared the performance of five genomic prediction models and two cross-validation methods. The five genomic models predicted EBV and de-regressed EBV of the ten traits similarly well. Of the two cross-validation methods, leave-one-out cross-validation maximized the number of animals at the stage of training for genomic prediction. Genomic prediction accuracy (GPA) on the ten quantitative traits was validated in 1,106 newly genotyped Brangus animals based on the SNP effects estimated in the previous set of 3,797 Brangus animals, and they were slightly lower than GPA in the original data. The present study was the first to leverage currently available genotype and phenotype resources in order to harness genomic prediction in Brangus beef cattle.

Hypertension, haematuria and renal functioning in haemophilia - a cross-sectional study in Europe.

BACKGROUND AND OBJECTIVES: This cross-sectional, epidemiological study sought to assess the prevalence and extent of potential risk factors for hypertension, particularly renal function related to haematuria and their associations in people with haemophilia. METHODOLOGY: Demographic and medical data were collected at a single time-point in patients with haemophilia over 40 years of age from 16 European centres. Associations with diagnosis of hypertension were tested in univariate and multivariate analyses. RESULTS: We enrolled 532 patients (median age 52 years, range 40-98) with haemophilia A (n = 467) or haemophilia B (n = 65). Haemophilia was severe (<0.01 IU mL-1 ) in 313 patients (59%). Hypertension was diagnosed in 239 patients (45%). In multivariate analyses, age and body mass index (BMI) were significantly and independently associated with hypertension (adjusted odds ratio (OR) 18.1, P < 0.001, in elderly patients and OR = 25.1, P < 0.001, in patients with BMI >30 kg m-2 ). Estimated glomerular filtration rate (eGFR) <70 mL min-1 (OR = 2.7, P = 0.047) was significantly associated with hypertension, but mean eGFR was significantly higher for severe than mild haemophilia. Further variables with OR > 2.8 were diabetes (OR = 2.8, P = 0.04), coronary artery disease (OR = 3.3, P = 0.052) and family history of hypertension (OR = 4.4, P < 0.001). Neither severity of haemophilia nor history of haematuria was significantly associated with hypertension in univariate or multivariate analyses. CONCLUSION: As in the general population, age and BMI were major risk factors for hypertension in people with haemophilia. Renal dysfunction was associated with hypertension, but the prevalence of renal dysfunction was not extensive and furthermore not significantly correlated with haematuria. The associations of other variables with hypertension require further studies to confirm causal relationships over time.

How to compare cardiovascular disease and risk factors in elderly patients with haemophilia with the general population.

INTRODUCTION: Studies on the prevalence of cardiovascular disease (CVD) and risk factors in patients with haemophilia (PWH) in comparison to the general population have generated inconsistent results. The ADVANCE Working Group collected data on CV comorbidities in PWH aged ≥40 years (H(3) Study). AIM: Identification of German epidemiological data on CVD for the general population, evaluation for appropriateness, and execution of comparisons with PWH. METHODS: Identification of data sources by structured literature (EMBASE, MEDLINE) searches. INCLUSION CRITERIA: German general population, CVD and risk factors, gender/age stratification, sample size >500 male persons, age groups ≥40 years, current data collection, language English/German. Comparison of data on CVD and risk factors in PWH (H(3)  Study) with published German general population data. RESULTS: Criteria for data source appropriateness were defined. Of five national and three international epidemiological studies, the DEGS1 Study (German Health Interview and Examination Survey for Adults) was identified as the most suitable comparator. Compared with men from DEGS1, hypertension was significantly more prevalent in PWH aged 50-59 years (41.7% [95% CI: 37.3-46.2] vs. 52.0% [95% CI: 43.7-60.1], P = 0.03). Coronary artery/heart disease (CHD) was significantly less prevalent in PWH aged ≥60 years (60-69 years: 19.5% [95% CI: 15.9-23.7] vs. 8.1% [95% CI: 3.3-16.1], P = 0.02; 70-79 years: 30.5% [95% CI: 25.9-35.5] vs. 11.8% [95% CI: 5.2-21.9], P = 0.002). No statistically significant difference for ischaemic cerebrovascular disease/stroke was detected. CONCLUSION: Increased prevalence of hypertension in PWH should trigger regular screening. CHD does occur in PWH aged ≥60 years though apparently with lower prevalence. Given the growing population of elderly PWH, guidelines for prevention and treatment of CVD should be developed.

CYP2A6 Effects on Subjective Reactions to Initial Smoking Attempt.

INTRODUCTION: In very novice smokers, CYP2A6 genotypes that reduce nicotine metabolism to an intermediate rate may increase smoking risk, relative to both normal and slow rates. The present study examined the hypothesis that intermediate metabolism variants are associated with greater pleasurable effects of the initial smoking attempt than either normal or slow metabolism variants. METHODS: Participants were novice smokers (N = 261, 65% female) of European descent. Predicted nicotine metabolic rate based on CYP2A6 diplotypes (CYP2A6 Diplotype Predicted Rate [CDPR]) was partitioned into Normal, Intermediate, and Slow categories using a metabolism metric. Subjective reactions to the initial smoking attempt were assessed by the Pleasurable Smoking Experiences (PSE) scale, which was collected within 3 years of the initial smoking attempt. The effect of CDPR on PSE was tested using a generalized linear model in which CDPR was dummy coded and Intermediate CDPR was the reference condition. Gender was included in the model as a control for higher PSE scores by males. RESULTS: Lower PSE scores were associated with Normal CDPR, ß = -0.34, P = .008, and Slow CDPR, ß = -0.52, P = .001, relative to Intermediate CDPR. CONCLUSIONS: Intermediate CDPR-enhanced pleasurable effects of the initial smoking attempt relative to other CYP2A6 variants. This finding is consistent with the hypothesis that the risk effect of Intermediate CDPR on early smoking is a function of optimal pleasurable effects. IMPLICATIONS: This study supports our recent hypothesis that CYP2A6 diplotypes that encode intermediate nicotine metabolism rate are associated with enhanced pleasurable events following the initial smoking attempt, compared with diplotypes that encode either normal or slow metabolism. This hypothesis was offered to account for our unexpected previous finding of enhanced smoking risk in very novice smokers associated with intermediate metabolism rate. Our new finding encourages further investigation of time-dependent relations between CYP2A6 effects and smoking motives, and it encourages laboratory study of the mechanisms underlying the initial smoking enhancement in novice smokers associated with intermediate metabolism.

CYP2A6 Longitudinal Effects in Young Smokers.

INTRODUCTION: The present study sought to identify time-dependent within-participant effects of CYP2A6 genotypes on smoking frequency and nicotine dependence in young smokers. METHODS: Predicted nicotine metabolic rate based on CYP2A6 diplotypes (CYP2A6 diplotype predicted rate [CDPR]) was partitioned into Normal, Intermediate, and Slow categories using a metabolism metric. Growth-curve models characterized baseline and longitudinal CDPR effects with data from eight longitudinal assessments during a 6-year period (from approximately age 16-22) in young smokers of European descent (N = 296, 57% female) who had smoked less than 100 cigarettes lifetime at baseline and more than that amount by Year 6. Phenotypes were number of days smoked during the previous 30 days and a youth version of the Nicotine Dependence Syndrome Scale (NDSS). A zero-inflated Poisson growth-curve model was used to account for the preponderance of zero days smoked. RESULTS: At baseline, Intermediate CDPR was a risk factor relative to both Normal and Slow CDPR for smoking frequency and the NDSS. Slow CDPR was associated with the highest probability of smoking discontinuation at baseline. However, due to CDPR time trend differences, by young adulthood these baseline effects had been reordered such that the greatest risks for smoking frequency and the NDSS were associated with Normal CDPR. CONCLUSIONS: Reduced metabolism CYP2A6 genotypes are associated with both risk and protective effects in novice smokers. However, differences in the time-by-CDPR effects result in a reordering of genotype effects such that normal metabolism becomes the risk variant by young adulthood, as has been reliably reported in older smokers.

Plasmonic nanostructured metal-oxide-semiconductor reflection modulators.

We propose a plasmonic surface that produces an electrically controlled reflectance as a high-speed intensity modulator. The device is conceived as a metal-oxide-semiconductor capacitor on silicon with its metal structured as a thin patch bearing a contiguous nanoscale grating. The metal structure serves multiple functions as a driving electrode and as a grating coupler for perpendicularly incident p-polarized light to surface plasmons supported by the patch. Modulation is produced by charging and discharging the capacitor and exploiting the carrier refraction effect in silicon along with the high sensitivity of strongly confined surface plasmons to index perturbations. The area of the modulator is set by the area of the incident beam, leading to a very compact device for a strongly focused beam (∼2.5 µm in diameter). Theoretically, the modulator can operate over a broad electrical bandwidth (tens of gigahertz) with a modulation depth of 3 to 6%, a loss of 3 to 4 dB, and an optical bandwidth of about 50 nm. About 1000 modulators can be integrated over a 50 mm(2) area producing an aggregate electro-optic modulation rate in excess of 1 Tb/s. We demonstrate experimentally modulators operating at telecommunications wavelengths, fabricated as nanostructured Au/HfO2/p-Si capacitors. The modulators break conceptually from waveguide-based devices and belong to the same class of devices as surface photodetectors and vertical cavity surface-emitting lasers.

Coagulation and Fibrinolytic Activity of Tenecteplase and Alteplase in Acute Ischemic Stroke.

BACKGROUND AND PURPOSE: We compared the fibrinolytic activity of tenecteplase and alteplase in patients with acute ischemic stroke, and explored the association between hypofibrinogenaemia and intracerebral hemorrhage. METHODS: Venous blood samples from a subgroup of participants in the Alteplase-Tenecteplase Trial Evaluation for Stroke Thrombolysis (ATTEST) study were obtained at pretreatment, 3 to 12 hours, and 24±3 hours post-intravenous thrombolysis for analyses of plasminogen, plasminogen activator inhibitor-1, d-dimer, factor V, fibrinogen, and fibrin(ogen) degradation products, in addition to routine coagulation assays. Related sample Wilcoxon signed-rank tests were used to test the within-group changes, and independent Mann-Whitney tests for between-group differences. RESULTS: Thirty patients were included (alteplase=14 and tenecteplase=16) with similar baseline demographics. Compared with baseline, alteplase caused significant hypofibrinogenaemia (P=0.002), prolonged prothrombin time (P=0.011), hypoplasminogenaemia (P=0.001), and lower factor V (P=0.002) at 3 to 12 hours after administration with persistent hypofibrinogenaemia at 24 hours (P=0.011), whereas only minor hypoplasminogenaemia (P=0.029) was seen in the tenecteplase group. Tenecteplase consumed less plasminogen (P<0.001) and fibrinogen (P=0.002) compared with alteplase. CONCLUSIONS: In patients with acute ischemic stroke, alteplase 0.9 mg/kg caused significant disruption of the fibrinolytic system, whereas tenecteplase 0.25 mg/kg did not, consistent with the trend toward lower intracerebral hemorrhage incidence with tenecteplase in the ATTEST study. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01472926.

Characterization of grating-coupled long range surface plasmon polariton membrane waveguides.

The first demonstration of grating-coupled long range surface plasmon polaritons in cladded free-standing membrane waveguides is presented. Two different waveguide structures are explored: the first is a gold (Au) stripe embedded in a thin Cytop free-standing membrane, the other being the same structure but with a thin palladium (Pd) over-layer. The waveguides are excited with integrated grating couplers designed for a working wavelength of 1550 nm. The waveguides are characterized by applying a cutback technique with the Au waveguide loss measured as 3.4 dB/mm and the Pd/Au waveguide loss as 57 dB/mm. The wavelength dependency of the weakly reflecting optical cavity is also observed with a free spectral range of ~3.6 nm and a finesse of 2.1.

Near infrared amplified spontaneous emission in a dye-doped polymeric waveguide for active plasmonic applications.

Near-infrared amplified spontaneous emission (ASE) from an optically-pumped dye-doped polymeric slab waveguide, consisting of IR-140 in PMMA on a glass substrate, has been characterised. The ASE gain was measured using the variable stripe length method. Linewidth narrowing with increasing pump intensity was observed, indicating ASE gain in this material. The effects of the dye concentration and pump intensity on the gain were investigated under linear operation. The maximum achieved gain coefficient is γ ~68 cm(-1) for a film with 0.8 wt % of IR-140 to PMMA for a pump intensity of 43.4 mJ/cm(2). The polarisation dependence of the ASE gain was also investigated by measuring the gain coefficient of orthogonal TE and TM modes and varying the pump polarisation relative to the amplifier length. It was observed that there is some degree of gain anisotropy when the pump polarisation is aligned perpendicular to the length, but that the gain was isotropic when the pump polarisation is aligned parallel the length. The applicability of IR-140 doped PMMA for active plasmonic applications is discussed.

Fabrication of a plasmonic modulator incorporating an overlaid grating coupler.

The fabrication of a novel plasmonic reflection modulator is presented and described. The modulator includes plasmon excitation using a diffraction grating coupler and is based on a metal-insulator-semiconductor structure on silicon. Fabrication includes a thin thermal oxide, a plasmonic metal surface defined by optical lithography, a metal grating coupler defined by overlaid e-beam lithography, a passivation layer with metalized vias, and electrical contacts. Physical characterization of intermediate structures is provided along with modulation measurements at λ0 ∼ 1550 nm which verify the concept.