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Item does not contain fulltext, BACKGROUND: This study aims to evaluate the predictive value of lymph nodes (LN) suspicious for metastases on preoperative prostate-specific membrane antigen (PSMA) PET/CT for biochemical persistence (BCP) and early biochemical recurrence (BCR) following robotic-assisted radical prostatectomy (RARP) with extended pelvic LN dissection (ePLND). METHODS: We evaluated 213 patients with intermediate and high-risk prostate cancer (PCa) who underwent clinical staging with preoperative (68)Ga- or (18)F-PSMA-PET/CT scan and subsequent RARP with ePLND. Patients were grouped as PSMA- or PSMA+ depending on their LN status on PSMA-PET/CT and subdivided according to histological LN status in pN0 or pN1. Diagnostic accuracy of PSMA-PET/CT for the detection of pN1 was evaluated. BCP was defined as a first postoperative serum PSA level ≥0.1 ng/mL 6-12 weeks following RP. Early BCR was defined as detectable PSA > 0.2 ng/mL within 12 months of follow-up. Univariable logistic regression analyses were used to evaluate the effect of PSMA+ on BCP and BCR. RESULTS: Forty patients (19%) were PSMA+. The overall incidence of pN1 was 23%. Sensitivity, specificity, PPV and NPV on a per patient level for the detection of pN1 was 29%, 84%, 35%, and 80% respectively. BCP was observed in 26 of 211 patients (12%) and early BCR in 23 of 110 patients (21%). The presence of PSMA+ was a significant predictor for BCP (OR 7.1, 2.9-17.1 95% CI) and BCR (OR 8.1, 2.9-22.6 95% CI). CONCLUSION: Preoperative PSMA-PET/CT may be a valuable tool for patient counseling for RARP and ePLND as it is a significant predictor for the risk of postoperative BCP and early BCR. We conclude that an ePLND should not be avoided in men with intermediate or high-risk PCa and preoperative negative PSMA-PET/CT, as 20% have microscopic LN metastasis.

Item does not contain fulltext, In recent years, clinical use of novel advanced imaging modalities in prostate cancer detection, staging, and therapy has intensified and is currently reforming clinical guidelines. In the future, advanced imaging technologies will continue to develop and become even more accurate, which will offer new opportunities for improving patient selection, surgical treatment, and radiotherapy, with the potential to guide prostate cancer therapy.

In Theoretical Biology, the Price Equation is a valuable tool to describe the change in average phenotype in a population. However, the Price Equation does not describe how migration affects the average phenotype in local populations. Furthermore, on larger time scales, the mathematical meaning of the terms in the Price Equation diverges from the intuitive interpretation of most people. Also, in Theoretical Biology, concepts like `long-term' selection versus `short-term' selection, as well as `local' versus `global' selection, are sometimes discussed, yet a precise mathematical framework to describe these concepts is missing. I am proposing such a framework by introducing several extensions to the Price Equation. With use of this framework, selection, as well as other factors that can cause the average phenotype in a population to change, can be described in an exact and unambiguous way on multiple scales in space and time.

Contains fulltext : 221400.pdf (publisher's version ) (Open Access), Firearm examination is subject to increased scrutiny regarding its foundational validity and inherent subjective nature. The increased use of automatic comparison systems may help to reduce subjectivity. In this paper, we present the performance and limits of an automatic comparison system that assigns a weight to the forensic findings for the comparisons between firing pin marks, breechface marks, or a combination of the two. This weight is expressed by a likelihood ratio (LR) based on 3D topographical measurements coupled with a bi-dimensional statistical model. As the performance of such systems may depend on the reference databases used to inform the model, we investigated the impact of the brand of ammunition and the number of samples. We show that reference databases used to calculate LRs should ideally consist of the same type of ammunition as is seen in the case under investigation and that 7 specimens fired by the same firearm are enough to obtain rates of misleading evidence of a similar magnitude compared to those obtained when far more specimens (60) are used. Additionally, the automatic system was used to assess the outcomes of 7 cases with known same-source or different-source ground truths. These cases were also examined by 8 qualified firearm examiners. In all cases, the experts’ appraisals were in line with the ground truth. The automatic system showed some limitations in cases were the data were not sufficient to calculate a robust LR, but also that it can assist and enhance the examiners in their decision process.

Contains fulltext : 190130.pdf (publisher's version ) (Open Access)

Item does not contain fulltext, Inflammatory bowel diseases (IBDs) are defined as chronic relapsing immune-mediated disorders of the gastrointestinal tract. IBD exacerbations are characterized by recruitment of mainly CXCL8 receptor-expressing activated neutrophils into the intestinal wall, leading to severe damage. Considering its chronic relapsing character, accurate and timely diagnosis of an exacerbation is pivotal for early adaptation of the treatment and reduction of the disease burden. However, endoscopic evaluation is invasive and associated with an increased risk of perforation. We previously developed a (99m)Tc-labeled CXCL8 preparation in preclinical models including colitis and clinical studies. METHODS: In this study, we investigate the accuracy of (99m)Tc-CXCL8 SPECT to detect and localize disease activity in a prospective series of patients with IBD. Thirty patients (15 Crohns disease, 15 ulcerative colitis) participated, and 92 segmental pairs of histology and (99m)Tc-CXCL8 scans were studied. Imaging was performed after injection of 400 MBq of (99m)Tc-CXCL8. Planar and SPECT images of the abdomen were acquired at 30 min and 4 h after the injection. RESULTS: The overall sensitivity and specificity on a per-patient basis for the detection of active disease were 95% and 44% for (99m)Tc-CXCL8 scan and 71% and 70% for endoscopy. The degree of (99m)Tc-CXCL8 accumulation correlated to the degree of neutrophilic influx in affected mucosa. Sensitivity and specificity on a per-segment basis, calculated from the 92 segmental pairs, were 82% and 72%, negative predictive value was 81%, and overall positive predictive value was 74%. Specificity could be increased at the expense of sensitivity using different cutoffs. In 74 segmental pairs, overall sensitivity and specificity for endoscopy were 74% and 85%, positive predictive value was 81%, and negative predictive value was 79%. CONCLUSION: (99m)Tc-CXCL8 SPECT provides a novel imaging technique to target neutrophil recruitment to the intestinal

Recent time-lapse microscopy experiments on bacterial growth have shown large cell-to-cell variations in growth rate and protein expression levels. Earlier experiments at the population level have shown that the expression of different classes of protein is tightly regulated to achieve fast growth in various conditions. We have built a coarse-grained model of bacterial metabolism that incorporates both the stochasticity of protein production and division, and the regulation that optimises growth. We introduce novel variables that quantify the coupling from gene expression to growth, which we call growth control coefficients. Analysis of the system in the optimal state shows that stochasticity in the growth rate has its main cause in the stochasticity of frequently occurring proteins, even though these fluctuate relatively little. The global regularity of protein expression is explained by optimising the system for growth rate. We include a regulatory mechanism in our model that achieves this in close approximation. The regulation also counteracts the growth-inhibiting effects of stochasticity, by lowering the amplitude and decorrelation time of fluctuations in the protein concentrations. We use the model to compute crosscorrelations between protein expression and growth rate. The resulting graphs reproduce several features present in their experimental counterparts.

This paper describes the current developments regarding cryogenic rocket engine technology at Delft Aerospace Rocket Engineering (DARE). DARE is a student society based at Delft University of Technology with the goal of being the first student group in the world to launch a rocket into space. After the launch of the hybrid engine powered Stratos II+ sounding rocket in October 2015, DARE decided to investigate highly efficient liquid rocket engine technology . In this context DARE initiated the cryogenic project with the goal of developing a liquid rocket engine using liquid oxygen and liquid methane as propellants with a nominal thrust in the order of 10kN. Eventually this engine shall power a future sounding rocket into space. As an intermediate step, a 3 kN class engine is being developed. Subsystem development tests and possibly a hot-fire test campaign on this engine are planned for 2016 and its development intends to provide DARE with the required experience and knowledge to develop large scale liquid rocket engines. The engine is developed in cooperation with Heliaq Advanced Engineering and is designed to meet the requirements of the second stage engine of the ALV reusable launch vehicle. The design is a pressure-fed engine, regeneratively cooled using the liquid methane fuel. After passing the coolant channels, the methane is injected into the combustion chamber in gaseous state together with the liquid oxygen in a co-axial manner. The engine is ignited by means of a pyrotechnic igniter using an ammonium perchlorate based propellant. During a test sequence, the propellants are stored in insulated run-tanks and are pressurized using helium. This paper describes the project objective, the current progress on the design and production, and finally four proposed research topics that are indented to be conducted at the faculty of Aerospace Engineering of Delft University of Technology., Space Systems Egineering

Item does not contain fulltext, OBJECTIVES: Respiratory motion artefacts during positron emission tomography (PET) deteriorate image quality, potentially introducing diagnostic uncertainties. The objective of this study was to determine the impact of optimal respiratory gating on clinical staging and management of patients with primary lung cancer. MATERIALS AND METHODS: From our fast-track outpatient diagnostic program, 55 patients with primary lung cancer, who underwent whole body [(18)F]-fluorodeoxyglucose (FDG) PET, were included. Respiratory gating was performed on bed positions covering the thorax and abdomen. Independent reading was conducted by two nuclear medicine physicians. The observers scored the number and anatomical location of the lesions, lymph node basins and the presence of distant metastasis in non-gated and gated images. A tumor (T), lymph node (N), and metastasis (M) stage was assigned to each patient according to the 7th revision of the TNM classification. Staging accuracy was determined using histopathological data and follow-up CT imaging. In addition, a management plan was created for each patient based on non-gated and gated images by an experienced pulmonologist. RESULTS: For nuclear medicine physician 1 and 2, respiratory gating resulted in detection of more lesions in five and eight patients (9% and 15%) respectively. However, this did not result in any migration in T or M-stage. Migration in N-stage was observed in four and seven patients (7% and 13%) for nuclear medicine physician 1 and 2 respectively. Staging accuracy was slightly improved when respiratory gating was performed. Furthermore, there was substantial agreement in patient management between non-gated and gated images. CONCLUSIONS: Respiratory gating improved staging accuracy, mainly in assessment of lymph node involvement. However, the effect on patient management was limited due to the presence of already advanced disease stage in many patients. These findings suggest that the expected impact of respira

Genetic mapping on fully sequenced individuals is transforming understanding of the relationship between molecular variation and variation in complex traits. Here we report a combined sequence and genetic mapping analysis in outbred rats that maps 355 quantitative trait loci for 122 phenotypes. We identify 35 causal genes involved in 31 phenotypes, implicating new genes in models of anxiety, heart disease and multiple sclerosis. The relationship between sequence and genetic variation is unexpectedly complex: at approximately 40% of quantitative trait loci, a single sequence variant cannot account for the phenotypic effect. Using comparable sequence and mapping data from mice, we show that the extent and spatial pattern of variation in inbred rats differ substantially from those of inbred mice and that the genetic variants in orthologous genes rarely contribute to the same phenotype in both species., Genetic mapping on fully sequenced individuals is transforming understanding of the relationship between molecular variation and variation in complex traits. Here we report a combined sequence and genetic mapping analysis in outbred rats that maps 355 quantitative trait loci for 122 phenotypes. We identify 35 causal genes involved in 31 phenotypes, implicating new genes in models of anxiety, heart disease and multiple sclerosis. The relationship between sequence and genetic variation is unexpectedly complex: at approximately 40% of quantitative trait loci, a single sequence variant cannot account for the phenotypic effect. Using comparable sequence and mapping data from mice, we show that the extent and spatial pattern of variation in inbred rats differ substantially from those of inbred mice and that the genetic variants in orthologous genes rarely contribute to the same phenotype in both species.

Contains fulltext : 96570.pdf (publisher's version ) (Open Access), BACKGROUND: Effective mass drug administration (MDA) with anti-malarial drugs can clear the human infectious reservoir for malaria and thereby interrupt malaria transmission. The likelihood of success of MDA depends on the intensity and seasonality of malaria transmission, the efficacy of the intervention in rapidly clearing all malaria parasite stages and the degree to which symptomatic and asymptomatic parasite carriers participate in the intervention. The impact of MDA with the gametocytocidal drug combination sulphadoxine-pyrimethamine (SP) plus artesunate (AS) plus primaquine (PQ, single dose 0.75 mg/kg) on malaria transmission was determined in an area of very low and seasonal malaria transmission in northern Tanzania. METHODS: In a cluster-randomized trial in four villages in Lower Moshi, Tanzania, eight clusters (1,110 individuals; cluster size 47- 209) were randomized to observed treatment with SP+AS+PQ and eight clusters (2,347 individuals, cluster size 55- 737) to treatment with placebo over three days. Intervention and control clusters were 1 km apart; households that were located between clusters were treated as buffer zones where all individuals received SP+AS+PQ but were not selected for the evaluation. Passive case detection was done for the entire cohort and active case detection in 149 children aged 1-10 year from the intervention arm and 143 from the control arm. Four cross-sectional surveys assessed parasite carriage by microscopy and molecular methods during a five-month follow-up period. RESULTS: The coverage rate in the intervention arm was 93.0% (1,117/1,201). Parasite prevalence by molecular detection methods was 2.2-2.7% prior to the intervention and undetectable during follow-up in both the control and intervention clusters. None of the slides collected during cross-sectional surveys had microscopically detectable parasite densities. Three clinical malaria episodes occurred in the intervention (n = 1) and control clusters (n = 2). CONCLUSI

Contains fulltext : 97761.pdf (publisher's version ) (Closed access), OBJECTIVE: At-term pregnancy-induced vasodilation is the resultant of endothelium-dependent vasodilation, decreased myogenic reactivity, increased compliance, and reduced sensitivity to vasoconstrictor agents. We hypothesized that these vascular changes are already present at mid-gestation. STUDY DESIGN: In 20 mid-pregnant and 20 nonpregnant Wistar Hannover rats, we measured vascular responses of isolated mesenteric arteries and kidney. RESULTS: In the pregnant rats compared with the nonpregnant rats, mesenteric flow-mediated vasodilation and renal perfusion flow increased 1.52-fold (from 47 +/- 5 to 31 +/- 4 muL/min) and 1.13-fold (from 12.8 +/- 0.1 to 14.4 +/- 0.1 mL/min), respectively. Nitric oxide inhibition reduced mesenteric flow-mediated vasodilation to a similar extent in the pregnant and nonpregnant rats; it completely blocked the pregnancy-induced increase in renal perfusion flow. Pregnancy did not change mesenteric artery sensitivity to phenylephrine, myogenic reactivity, nor vascular compliance. CONCLUSION: At mid-gestation, alterations in rat mesenteric vascular tone depend primarily on flow-mediated endothelium-dependent changes and not on changes in alpha-adrenergic vasoconstrictor sensitivity, myogenic reactivity, or vascular compliance.

Aerospace Engineering

The TP53 tumor suppressor gene is mutated in the majority of human cancers. Inactivation of p53 in a variety of animal models results in early-onset tumorigenesis, reflecting the importance of p53 as a gatekeeper tumor suppressor. We generated a mutant Tp53 allele in the rat using a target-selected mutagenesis approach. Here, we report that homozygosity for this allele results in complete loss of p53 function. Homozygous mutant rats predominantly develop sarcomas with an onset of 4 months of age with a high occurrence of pulmonary metastases. Heterozygous rats develop sarcomas starting at 8 months of age. Molecular analysis revealed that these tumors exhibit a loss-of-heterozygosity of the wild-type Tp53 allele. These unique features make this rat highly complementary to other rodent p53 knockout models and a versatile tool for investigating tumorigenesis processes as well as genotoxic studies., The TP53 tumor suppressor gene is mutated in the majority of human cancers. Inactivation of p53 in a variety of animal models results in early-onset tumorigenesis, reflecting the importance of p53 as a gatekeeper tumor suppressor. We generated a mutant Tp53 allele in the rat using a target-selected mutagenesis approach. Here, we report that homozygosity for this allele results in complete loss of p53 function. Homozygous mutant rats predominantly develop sarcomas with an onset of 4 months of age with a high occurrence of pulmonary metastases. Heterozygous rats develop sarcomas starting at 8 months of age. Molecular analysis revealed that these tumors exhibit a loss-of-heterozygosity of the wild-type Tp53 allele. These unique features make this rat highly complementary to other rodent p53 knockout models and a versatile tool for investigating tumorigenesis processes as well as genotoxic studies.

Item does not contain fulltext, Microscopic detection of Plasmodium vivax gametocytes, the sexual life stage of this malaria parasite, is insensitive because P. vivax parasitaemia is low. To detect and quantify gametocytes a more sensitive, quantitative real-time Pvs25-QT-NASBA based on Pvs25 mRNA was developed and tested in two clinical sample sets from three different continents. Pvs25-QT-NASBA is highly reproducible with low inter-assay variation and reaches sensitivity approximately 800 times higher than conventional microscopic gametocyte detection. Specificity was tested in 104 samples from P. vivax-, P. falciparum-, P. malariae-, and P. ovale-infected patients. All non-vivax samples were negative in the Pvs25-QT-NASBA; out of 74 PvS18-QT-NASBA positive samples 69% were positive in the Pvs25-QT-NASBA. In a second set of 136 P. vivax microscopically confirmed samples, gametocyte prevalence was 8%, whereas in contrast 66% were positive by Pvs25-QT-NASBA. The data suggest that the human P. vivax gametocyte reservoir is much larger when assessed by Pvs25-QT-NASBA than by microscopy.

Contains fulltext : 80229.pdf (publisher's version ) (Closed access), MDMA (3,4-methylenedioxymethamphetamine or "ecstasy") is a recreationally used drug with remarkable and characteristic prosocial effects. In spite of abundant attention in the scientific literature, the mechanism of its prosocial effects has not been elucidated in humans. Recently, research in animals has suggested that the neuropeptide oxytocin may induce these effects. In a double blind, randomized, crossover, and placebo-controlled study in 15 healthy volunteers we assessed blood oxytocin and MDMA concentrations and subjective prosocial effects after oral administration of 100 mg MDMA or placebo. MDMA induced a robust increase of blood oxytocin concentrations and an increase of subjective prosocial feelings. Within subjects, the variations in these feelings were significantly and positively correlated with variation in oxytocin levels, and the correlations between these feelings and oxytocin were significantly stronger than those between these feelings and blood MDMA levels. MDMA induces oxytocin release in humans, which may be involved in the characteristic prosocial effects of ecstasy.

Contains fulltext : 71100.pdf (publisher's version ) (Open Access), BACKGROUND: Plasmodium falciparum Apical Membrane Antigen 1 (PfAMA1) is a candidate vaccine antigen expressed by merozoites and sporozoites. It plays a key role in red blood cell and hepatocyte invasion that can be blocked by antibodies. METHODOLOGY/PRINCIPAL FINDINGS: We assessed the safety and immunogenicity of recombinant PfAMA1 in a dose-escalating, phase Ia trial. PfAMA1 FVO strain, produced in Pichia pastoris, was reconstituted at 10 microg and 50 microg doses with three different adjuvants, Alhydrogel, Montanide ISA720 and AS02 Adjuvant System. Six randomised groups of healthy male volunteers, 8-10 volunteers each, were scheduled to receive three immunisations at 4-week intervals. Safety and immunogenicity data were collected over one year. Transient pain was the predominant injection site reaction (80-100%). Induration occurred in the Montanide 50 microg group, resulting in a sterile abscess in two volunteers. Systemic adverse events occurred mainly in the AS02 groups lasting for 1-2 days. Erythema was observed in 22% of Montanide and 59% of AS02 group volunteers. After the second dose, six volunteers in the AS02 group and one in the Montanide group who reported grade 3 erythema (>50 mm) were withdrawn as they met the stopping criteria. All adverse events resolved. There were no vaccine-related serious adverse events. Humoral responses were highest in the AS02 groups. Antibodies showed activity in an in vitro growth inhibition assay up to 80%. Upon stimulation with the vaccine, peripheral mononuclear cells from all groups proliferated and secreted IFNgamma and IL-5 cytokines. CONCLUSIONS/SIGNIFICANCE: All formulations showed distinct reactogenicity profiles. All formulations with PfAMA1 were immunogenic and induced functional antibodies. TRIAL REGISTRATION: (Clinicaltrials.gov) NCT00730782.

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Contains fulltext : 23155.PD.PDF (publisher's version ) (Open Access)

It was previously demonstrated that a conductive flame with a suitable arrangement of electrodes and coupling circuitry can transform an electrical signal into a high level acoustic output at audible and ultrasonic frequencies. Experimental evidence also indicated that complex effects involving the optical and electromagnetic spectrum took place concurrently. The objective of this research was to obtain a fundamental understanding of the observed phenomena to allow evaluation of potential applications in the fields of combustion instability, noise suppression, ultrasonic sound generation, communications and RF effects. Data on the acoustic, optical, electrical, and microwave scattering properties of a seeded oxygen-acetylene flame were obtained over the frequency range up to 150 kHz. A theoretical model was developed which correctly predicts the frequency dependent electrical impedance of the flame and the amplitude and directivity of the external sound field. (Author)

An experimental investigation of the vapor-phase combustion of aluminum and beryllium was undertaken using electrically vaporized wires as the source of hightemperature, high-pressure metal vapor. Specifically investigated were (1) the overall reaction rates for the conversion of metal vapor to condensed oxide; (2) the significant species which are present and may act as reaction intermediates; and (3) the detailed mechanism of the combustion including the nucleation and growth of condensed oxide particles. (Author)