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SummaryGenome-wide association studies (GWAS) in microbes face different challenges to eukaryotes and have been addressed by a number of different methods. pyseer brings these techniques together in one package tailored to microbial GWAS, allows greater flexibility of the input data used, and adds new methods to interpret the association results.Availability and Implementationpyseer is written in python and is freely available at https://github.com/mgalardini/pyseer, or can be installed through pip. Documentation and a tutorial are available at http://pyseer.readthedocs.io.Contactjohn.lees@nyumc.org and marco@ebi.ac.ukSupplementary informationSupplementary data are available online.

Fibrodysplasia ossificans progressiva (FOP) is a rare autosomal-dominant disorder characterized by progressive and profoundly disabling heterotopic ossification (HO). Here we show that fibro/adipogenic progenitors (FAPs) are a major cell-of-origin of HO in an accurate genetic mouse model of FOP (Acvr1tnR206H). Targeted expression of the disease-causing type I bone morphogenetic protein (BMP) receptor, ACVR1(R206H), to FAPs recapitulates the full spectrum of HO observed in FOP patients. ACVR1(R206H)-expressing FAPs, but not wild-type FAPs, activate osteogenic signaling in response to activin ligands. Conditional loss of the wild-type Acvr1 allele dramatically exacerbates FAP-directed HO, suggesting that mutant and wild-type ACVR1 receptor complexes compete for activin ligands or type II BMP receptor binding partners. Finally, systemic inhibition of activin A completely blocks HO and restores wild-type-like behavior to transplanted Acvr1R206H/+ FAPs. Understanding the cells that drive HO may facilitate the development of cell-specific therapeutic approaches to inhibit catastrophic bone formation in FOP., Fibrodysplasia ossificans progressiva is a severe disorder characterized by heterotopic ossification, and is caused by mutations in ACVR1. Here, the authors show that expression of mutant ACVR1 in fibro/adipogenic progenitors recapitulates disease progression, and that this can be halted by systemic inhibition of activin A in mice.

Streptococcus pneumoniae is a common nasopharyngeal colonizer, but can also cause lifethreatening invasive diseases such as empyema, bacteremia and meningitis. Genetic variation of host and pathogen is known to play a role in invasive pneumococcal disease, though to what extent is unknown. In a genome-wide association study of human and pathogen we show that human variation explains almost half of variation in susceptibility to pneumococcal meningitis and one-third of variation in severity, and identified variants in CCDC33 associated with susceptibility. Pneumococcal variation explained a large amount of invasive potential, but serotype explained only half of this variation. Newly developed methods identified pneumococcal genes involved in invasiveness including pspC and zmpD, and allowed a human-bacteria interaction analysis, finding associations between pneumococcal lineage and STK32C.

The potential for genome-wide modeling of epistasis has recently surfaced given the possibility of sequencing densely sampled populations and the emerging families of statistical interaction models. Direct coupling analysis (DCA) has earlier been shown to yield valuable predictions for single protein structures, and has recently been extended to genome-wide analysis of bacteria, identifying novel interactions in the co-evolution between resistance, virulence and core genome elements. However, earlier computational DCA methods have not been scalable to enable model fitting simultaneously to 104-105polymorphisms, representing the amount of core genomic variation observed in analyses of many bacterial species. Here we introduce a novel inference method (SuperDCA) which employs a new scoring principle, efficient parallelization, optimization and filtering on phylogenetic information to achieve scalability for up to 105polymorphisms. Using two large population samples ofStreptococcus pneumoniae, we demonstrate the ability of SuperDCA to make additional significant biological findings about this major human pathogen. We also show that our method can uncover signals of selection that are not detectable by genome-wide association analysis, even though our analysis does not require phenotypic measurements. SuperDCA thus holds considerable potential in building understanding about numerous organisms at a systems biological level.Author SummaryRecent work has demonstrated the emerging potential in statistical genome-wide modeling to uncover co-selection and epistatic interactions between polymorphisms in bacterial chromosomes from densely sampled population data. Here we develop the Potts model based approach further into a fully mature computational method which can be applied to most existing bacterial population genomic data sets in a straightforward manner. Our advances are relying on more efficient parameter scoring, highly optimized and parallelized open source C++ code, which does not rely on the computation-intensive polymorphism subsampling approximations used earlier. By analyzing the two largest available population samples ofStreptococcus pneumoniae(the pneumococcus), we highlight several biological discoveries related to the survival of the pneumococcus and co-evolution of penicillin-binding loci, which were not uncovered by the earlier analyses. Our method holds considerable potential for building understanding about numerous organisms at a systems biological level.

Streptococcus pneumoniaeis a leading cause of invasive disease in infants, especially in low-income settings. Asymptomatic carriage in the nasopharynx is a prerequisite for disease, and the duration of carriage is an important consideration in modelling transmission dynamics and vaccine response. Existing studies of carriage duration variability are based at the serotype level only, and do not probe variation within lineages or fully quantify interactions with other environmental factors.Here we developed a model to calculate the duration of carriage episodes from longitudinal swab data. By combining these results with whole genome sequence data we estimate that pneumococcal genomic variation accounted for 63% of the phenotype variation, whereas host traits accounted for less than 5%. We further partitioned this heritability into both lineage and locus effects, and quantified the amount attributable to the largest sources of variation in carriage duration: serotype (17%), drug-resistance (9%) and other significant locus effects (7%). For the locus effects, a genome-wide association study identified 16 loci which may have an effect on carriage duration independent of serotype. Hits at a genome-wide level of significance were to prophage sequences, suggesting infection by such viruses substantially affects carriage duration.These results show that both serotype and non-serotype specific effects alter carriage duration in infants and young children and are more important than other environmental factors such as host genetics. This has implications for models of pneumococcal competition and antibiotic resistance, and leads the way for the analysis of heritability of complex bacterial traits.Significance statementOther than serotype, the genetic determinants of pneumococcal carriage duration are unknown. In this study we used longitudinal sampling to measure the duration of carriage in infants, and searched for any associated variation in the pan-genome. While we found that the pathogen genome explains most of the variability in duration, serotype did not fully account for this. Recent theoretical work has proposed the existence of alleles which alter carriage duration to explain the puzzle of continued coexistence of antibiotic-resistant and sensitive strains. Here we have shown that these alleles do exist in a natural population, and also identified candidates for the loci which fulfil this role. Together these findings have implications for future modelling of pneumococcal epidemiology and resistance.

The development of low profile gamma-ray detectors has encouraged the production of small field of view (SFOV) hand-held imaging devices for use at the patient bedside and in operating theatres. Early development of these SFOV cameras was focussed on a single modality—gamma ray imaging. Recently, a hybrid system—gamma plus optical imaging—has been developed. This combination of optical and gamma cameras enables high spatial resolution multi-modal imaging, giving a superimposed scintigraphic and optical image. Hybrid imaging offers new possibilities for assisting clinicians and surgeons in localising the site of uptake in procedures such as sentinel node detection. The hybrid camera concept can be extended to a multimodal detector design which can offer stereoscopic images, depth estimation of gamma-emitting sources, and simultaneous gamma and fluorescence imaging. Recent improvements to the hybrid camera have been used to produce dual-modality images in both laboratory simulations and in the clinic. Hybrid imaging of a patient who underwent thyroid scintigraphy is reported. In addition, we present data which shows that the hybrid camera concept can be extended to estimate the position and depth of radionuclide distribution within an object and also report the first combined gamma and Near-Infrared (NIR) fluorescence images.

Recent studies have provided evidence for rapid pathogen genome diversification, some of which could potentially affect the course of disease. We have previously described such variation seen between isolates infecting the blood and cerebrospinal fluid (CSF) of a single patient during a case of bacterial meningitis. Here, we performed whole-genome sequencing of paired isolates from the blood and CSF of 869 meningitis patients to determine whether such variation frequently occurs between these two niches in cases of bacterial meningitis. Using a combination of reference-free variant calling approaches, we show that no genetic adaptation occurs in either invaded niche during bacterial meningitis for two major pathogen species, Streptococcus pneumoniae and Neisseria meningitidis. This study therefore shows that the bacteria capable of causing meningitis are already able to do this upon entering the blood, and no further sequence change is necessary to cross the blood–brain barrier. Our findings place the focus back on bacterial evolution between nasopharyngeal carriage and invasion, or diversity of the host, as likely mechanisms for determining invasiveness.

A handheld, high-resolution small field of view (SFOV) pinhole gamma camera has been characterised using a new set of protocols adapted from standards previously developed for large field of view (LFOV) systems. Parameters investigated include intrinsic and extrinsic spatial resolution, spatial linearity, uniformity, sensitivity, count rate capability and energy resolution. Camera characteristics are compared to some clinical LFOV gamma cameras and also to other SFOV cameras in development.

Objectives Listeria monocytogenes is a food-borne pathogen that can cause meningitis. The listerial genotype ST6 has been linked to increasing rates of unfavourable outcome over time. We investigated listerial genetic variation and the relation with clinical outcome in meningitis. Methods We sequenced 96 isolates from adults with listerial meningitis included in two prospective nationwide cohort studies by whole genome sequencing, and evaluated associations between bacterial genetic variation and clinical outcome. We validated these results by screening listerial genotypes of 445 cerebrospinal fluid and blood isolates from patients over a 30-year period from the Dutch national surveillance cohort. Results We identified a bacteriophage, phiLMST6 co-occurring with a novel plasmid, pLMST6, in ST6 isolates to be associated with unfavourable outcome in patients (p 2.83e-05). The plasmid carries a benzalkonium chloride tolerance gene, emrC, conferring decreased susceptibility to disinfectants used in the food-processing industry. Isolates harbouring emrC were growth inhibited at higher levels of benzalkonium chloride (median 60 mg/L versus 15 mg/L; p

For intraoperative medical imaging, the development of small field of view (SFOV) hybrid gamma cameras is an expanding area of research. The performance characteristics of a new innovation combining both gamma and optical imaging in a co-aligned configuration, the Hybrid Gamma Camera (HGC) have been evaluated and compared. In this study the HGC was fitted with either 1500 μm thick columnar CsI:TI or 1500 μm thick pixelated GOS scintillators. The columnar CsI:TI scintillator has an intrinsic spatial resolution of 230 μm compared to 1090 μm for the pixelated GOS scintillator. The sensitivity at 140.5 keV of the CsI:TI was 40 %, however, for the GOS it was 54 %. The intrinsic spatial uniformity was comparable for both CsI:TI and GOS scintillators. There was a significant difference between the CsI:TI and GOS scintillators for count rate capability which was lower when using a GOS scintillator.

OBJECTIVE: To examine the imaging capability of a novel small field of view hybrid gamma camera (HGC) using (125)I seeds prior to surgical use. METHODS: The imaging performance of the camera system was assessed quantitatively and qualitatively at different source depths, source to collimator distances (SCD), activity levels, acquisition times and source separations, utilising bespoke phantoms. RESULTS: The system sensitivity and spatial resolution of the HGC for (125)I were 0.41 cps/MBq (at SCD 48 mm) and 1.53 ± 0.23 mm (at SCD 10 mm) respectively. The camera was able to detect the (125)I seed at a SCD of 63 mm (with no scattering material in place) in images recorded within a 1-min acquisition time. The detection of the seeds beneath scattering material (simulating deep-seated tumours) was limited to depths of less than 20 mm beneath the skin surface with a SCD of 63 mm and seed activity of 2.43 MBq. Subjective assessments of the hybrid images acquired showed the capability of the HGC for localising the (125)I seeds. CONCLUSION: This preliminary ex vivo study demonstrates that the HGC is capable of detecting (125)I seeds and could be a useful tool in radioactive seed localisation with the added benefit of providing hybrid optical γ images for guiding breast conserving surgery. ADVANCES IN KNOWLEDGE: The SFOV HGC could provide high resolution fused optical-gamma images of (125)I radioactive seeds indicating the potential use in intraoperative surgical procedure such as RSL.

Mathematical and computational techniques are developed for the analysis of annual MOT (roadworthiness) test data that the UK Department for Transport has placed in the public domain. This paper focusses on the development of a new theory which has the potential to estimate fine-scale temporal variations (e.g., monthly) in vehicle mileage at a population level, that we call the spot rate — derived from coarse-scale (e.g., annual) mileage data at an individual vehicle level. Due to the availability of data, the focus is on the UK situation, but the theory has applications to any data set internationally, where odometer readings of individual vehicles are monitored on an occasional basis. Numerical time-stepping schemes are derived from the theory and are tested on synthetic data to permit comparison with a known ground-truth mileage rate. It is found that for practical applicability, the methods need to pre-process data with smoothing filters (a full investigation of which is beyond the scope of this paper). Finally, we consider first steps in applying the methods directly to the MOT data set and the remaining problems that must be solved for them to become a practical reality.

Personal Rapid Transit (PRT) is an emerging urban transport mode. A PRT system operates much like a conventional hackney taxi system, except that the vehicles are driven by computer (no human driver) between stations in a dedicated network of guideways. The world’s first two PRT systems began operating in 2010 and 2011. In both PRT and taxi systems, passengers request immediate service; they do not book ahead. Perfect information about future requests is therefore not available, but statistical information about future requests is available from historical data. If the system does not use this statistical information to position empty vehicles in anticipation of future requests, long passenger waiting times result, which makes the system less attractive to passengers, but using it gives rise to a difficult stochastic optimisation problem. This paper develops three lower bounds on achievable mean passenger waiting time, one based on queuing theory, one based on the static problem, in which it is assumed that perfect information is available, and one based on a Markov Decision Process model. An evaluation of these lower bounds, together with a practical heuristic developed previously, in simulation shows that these lower bounds can often be nearly attained, particularly when the fleet size is large. The results also show that low waiting times and high utilisation can be simultaneously obtained when the fleet size is large, which suggests important economies of scale.

Recent studies have provided evidence for rapid pathogen genome variation, some of which could potentially affect the course of disease. We have previously detected such variation by comparing isolates infecting the blood and cerebrospinal fluid (CSF) of a single patient during a case of bacterial meningitis.To determine whether the observed variation repeatedly occurs in cases of disease, we performed whole genome sequencing of paired isolates from blood and CSF of 938 meningitis patients. We also applied the same techniques to 54 paired isolates from the nasopharynx and CSF.Using a combination of reference-free variant calling approaches we show that no genetic adaptation occurs in the invasive phase of bacterial meningitis for four major pathogen species:Streptococcus pneumoniae, Neisseria meningitidis, Listeria monocytogenes and Haemophilus influenzae. From nasopharynx to CSF, no adaptation was seen inS. pneumoniae, but inN. meningitidismutations potentially mediating adaptation to the invasive niche were occasionally observed in thedcagene.This study therefore shows that the bacteria capable of causing meningitis are already able to do this upon entering the blood, and no further sequence change is necessary to cross the blood-brain barrier. The variation discovered from nasopharyngeal isolates suggest that larger studies comparing carriage and invasion may help determine the likely mechanisms of invasiveness.Author SummaryWe have analysed the entire DNA sequence from bacterial pathogen isolates from cases of meningitis in 938 Dutch adults, focusing on comparing pairs of isolates from the patient’s blood and their cerebrospinal fluid. Previous research has been on only a single patient, but showed possible signs of adaptation to treatment within the host over the course of a single case of disease.By sequencing many more such paired samples, and including four different bacterial species, we were able to determine that adaptation of the pathogen does not occur after bloodstream invasion during bacterial meningitis.We also analysed 54 pairs of isolates from pre- and post-invasive niches from the same patient. InN. meningitidiswe found variation in the sequence of one gene which appears to provide bacteria with an advantage after invasion of the bloodstream.Overall, our findings indicate that evolution after invasion in bacterial meningitis is not a major contribution to disease pathogenesis. Future studies should involve more extensive sampling between the carriage and disease niches, or on variation of the host.

Legionella pneumophila is an environmental bacterium and the leading cause of Legionnaires’ disease. Just five sequence types (ST), from more than 2000 currently described, cause nearly half of disease cases in northwest Europe. Here, we report the sequence and analyses of 364 L. pneumophila genomes, including 337 from the five disease-associated STs and 27 representative of the species diversity. Phylogenetic analyses revealed that the five STs have independent origins within a highly diverse species. The number of de novo mutations is extremely low with maximum pairwise single-nucleotide polymorphisms (SNPs) ranging from 19 (ST47) to 127 (ST1), which suggests emergences within the last century. Isolates sampled geographically far apart differ by only a few SNPs, demonstrating rapid dissemination. These five STs have been recombining recently, leading to a shared pool of allelic variants potentially contributing to their increased disease propensity. The oldest clone, ST1, has spread globally; between 1940 and 2000, four new clones have emerged in Europe, which show long-distance, rapid dispersal. That a large proportion of clinical cases is caused by recently emerged and internationally dispersed clones, linked by convergent evolution, is surprising for an environmental bacterium traditionally considered to be an opportunistic pathogen. To simultaneously explain recent emergence, rapid spread and increased disease association, we hypothesize that these STs have adapted to new man-made environmental niches, which may be linked by human infection and transmission.

A random path length model for X-ray avalanche photodiodes (APDs) has been used to assess the effects of carriers' dead spaces and injection position on the avalanche gain distributions. Significant carrier's dead space, typically found in submicrometer avalanche regions, is found to reduce spread in the avalanche gain distribution, which is consistent with the reduced excess noise factors observed in conventional APDs. Mixed carrier-type injection increases the spread in the gain distribution along the avalanche region. The model was validated by comparing the results with experimental X-ray spectra from a GaAs/ Al0.8Ga0.2As separate absorption and multiplication APD. Good agreement was achieved between measured and simulated data. Avalanche multiplication shifted the detected photo peak away from the system noise, thereby improving its energy resolution and signal-to-noise ratio.

The empty vehicle redistribution (EVR) problem is to decide when and where to move empty vehicles in a Personal Rapid Transit or taxi system. These decisions are made in real time by an EVR algorithm. A reactive EVR algorithm moves empty vehicles only in response to known requests; in contrast, a proactive EVR algorithm moves empty vehicles in anticipation of future requests. This paper describes two new proactive EVR algorithms, called sampling and voting (SV) and dynamic transportation problem (DTP), that move empty vehicles proactively based on demand estimates from historical data. It also develops methods for assessing the performance of EVR algorithms absolutely in terms of both throughput and passenger waiting times. In simulation tests, the proposed algorithms provide lower passenger waiting times than other algorithms in the literature, and proactive movement of empty vehicles significantly reduces waiting times, usually with a modest increase in empty vehicle travel.

Circular mesa GaAs p+–i–n+ diodes for photon counting soft X-ray spectroscopy have been fabricated and characterised over a temperature range of +80 to –30 °C. The spectroscopic performance of the diodes, as measured by the FWHM of the Mn Kα X-ray line from an 55Fe radioisotope, is reported. In addition, we compare the GaAs diodes with previously fabricated and characterised Al0.8Ga0.2As p+–i–n+ diodes of similar geometry.

Realistic Monte Carlo simulations for the avalanche gain of absorbed X-ray photons were carried out in a study of the relationship between avalanche gain and energy resolution for semiconductor X-ray avalanche photodiodes (APDs). The work explored how the distribution of gains, which directly affects the energy resolution, depends on the number of injected electron-hole pairs (and, hence, the photon energy), the relationship between ionization coefficients, and the mean gain itself. We showed that the conventional notion of APD gains significantly degrading energy resolution is incomplete. If the X-ray photons are absorbed outside the avalanche region, then high avalanche gains with little energy resolution penalty can be achieved using dissimilar ionization coefficients. However, absorption of X-ray photons within the avalanche region will always result in broad gain distribution (degrading energy resolution), unless electrons and holes have similar ionization coefficients.

Detectors capable of withstanding high radiation environments for prolonged periods of exposure are essential for the monitoring of nuclear power stations and nuclear waste as well as for space exploration. Schottky diode X-ray detectors were exposed to high dose proton irradiation (1013 cm-2, 50 MeV) and changes in the detection resolution (spectroscopic full width half-maximum) have been observed. Using Deep Level Transient Spectroscopy (DLTS) and the degradation of the electrical characteristics of the diode, we have shown that radiation induced traps located in the upper half of the bandgap have reduced the concentration of carriers.

A personal rapid transit (PRT) system uses compact, computer-guided vehicles running on dedicated guideways to carry individuals or small groups directly between pairs of stations. PRT vehicles operate on demand when a passenger requests service at his or her origin station. Because the number of trips requested from a station need not equal the number of trips ending there, some empty vehicles must move to balance the flows. The empty vehicle redistribution (EVR) problem prompts the decision to move empty vehicles reactively in response to known requests or proactively in anticipation of requests. This paper develops a new algorithm for the EVR problem called “sampling and voting” (SV). SV results in the choice of reactive movements with the use of a simple nearest-neighbor rule; the selection of proactive movements is derived by the generation of an ensemble of possible sequences of future passenger requests, the solution of a deterministic optimization problem for each sequence individually, and the discovery of the empty vehicle movements that are common among the sequences. Moving vehicles proactively is essential for providing short passenger waiting times. The new SV algorithm was tested in simulation with several case study systems, and it produced significantly shorter passenger waiting times than did existing EVR algorithms. Variants of the SV method developed here for PRT are also applicable to conventional taxi systems and emergency response systems.

A personal rapid transit system uses compact, computer-guided vehicles running on dedicated guideways to carry individuals or small groups directly between pairs of stations. Vehicles move on demand when a passenger requests service at his or her origin station. Because the number of trips requested from a station need not equal the number of trips ending there, some vehicles must run empty to balance the flows. The empty vehicle redistribution (EVR) problem is to decide which empty vehicles to move and when and where to move them; an EVR algorithm makes these decisions in real time, as passengers arrive and request service. A method was developed for finding the theoretical maximum demand (with a given spatial distribution) that a given system could serve with any EVR algorithm, which provides a benchmark against which particular EVR algorithms can be compared. The maximum passenger demand that a particular EVR algorithm can serve can be determined by simulation and then compared with the benchmark. The method is applied to two simple EVR heuristics on two example systems. The results suggest that this is a useful method for determining the strengths and weaknesses of a variety of EVR heuristics across a range of networks, passenger demands, and fleet sizes.

A Monte Carlo model has been developed to predict the X-ray spectroscopic performance of silicon carbide detectors over the energy range 1–60 keV. Consideration of the charge creation and diffusion in the different active layers along with provision for fluorescence and Compton scattering produce spectra that are in good agreement with measurements. Direct comparison of modelled spectra with X-ray data from a novel detector, the Semi-Transparent SiC Schottky Diode (STSSD) and comparison of SiC data from the literature also shows good agreement between the reported spectra and the model. Predicted quantum efficiencies are also presented.

Al0.8Ga0.2As p+–p−–n+ diodes with low reverse leakage currents ( 20 V), we observed avalanche multiplication which, while improving the signal-to-noise ratio, degraded the spectroscopic performance.

We describe a novel SiC Schottky diode architecture. The semi-transparent SiC Schottky diode has an “ultra-thin” (18 nm Ni/Ti) Schottky contact, a gold annular overlayer and a gold corner-contact pad. We show that the new architecture exhibits the same essential characteristics as a more conventional ‘thick-contact’ Schottky diode (≥ 100nm). Such diodes will have a higher efficiency for low energy (< 5 keV) X-rays than that of conventional structures combined with minimal self-fluorescence from the electrode materials. We present X-ray spectra from 55 Fe, 109 Cd and 241 Am radioactive sources that show these diodes can be used for spectroscopy with promising energy resolution (1.47 keV FWHM at 22 keV) at room temperature (23oC). The reduction in contact thickness, however, does reduce the barrier height of the new diodes in comparison to those fabricated using the conventional process, and requires a trade-off between the low energy detection threshold and the noise in the detector.

We describe the development of a scintillator-coated charge coupled device (CCD) based camera for imaging small volumes of radionuclide uptake in tissues. The high resolution gamma imager (HRGI) is a collimated, scintillator-coated, low cost, high performance imager using low noise CCDs. The HRGI operates in photon counting mode using a peltier cooler to achieve an operating temperature of 0/spl deg/C. We have measured the spatial resolution and efficiency of a prototype CCD from e2v Technologies Ltd coated with a 500/spl mu/m thick Gadox (Gd2O2S(Tb)) layer using 59.5 keV radiation from a /sup 241/Am source and 140 keV gamma-rays from a /sup 99m/Tc source. We also describe our first images using /sup 99m/Tc phantoms.

The high resolution gamma imager (HRGI): a CCD based camera for medical imaging. We describe the High Resolution Gamma Imager (HRGI): a Charge Coupled Device (CCD) based camera for imaging small volumes of radionuclide uptake in tissues. The HRGI is a collimated, scintillator-coated, low cost, high performance imager using low noise CCDs that will complement whole-body imaging Gamma Cameras in nuclear medicine. Using 59.5 keV radiation from a Am-241 source we have measured the spatial resolution and relative efficiency of test CCDs from E2V Technologies (formerly EEV Ltd.) coated with Gadox (Gd2O2S(Tb)) layers of varying thicknesses. The spatial resolution degrades from 0.44 to 0.6mm and the detection efficiency increases ( x 3) as the scintillator thickness increases from 100 to 500 mum. We also describe our first image using the clinically important isotope Tc-99m. The final HRGI will have intrinsic sub-mm spatial resolution (similar to 0.7 mm) and good energy resolution over the energy range 30-160 keV. (C) 2003 Elsevier B.V. All rights reserved.

Ed. Note: The author of the published article did not feel that a response was necessary . After the pde1 gene was found to be essential for growth in an experimental meningitis model ([1][1]), Cron et al. further showed in a 2011 study that Streptococcus pneumoniae mutants with pde1 (SP2205 in

We investigated how preferred and nonpreferred tastes influence the disposition of fat. Adult male Sprague Dawley rats were infused with 5 ml of 20% intralipid through an intragastric catheter and with 0.3 ml of a taste solution through an intraoral catheter. At 120 min postinfusion, plasma concentrations of fat fuels (triglycerides and non-esterified fatty acids) were either unchanged or slightly higher after rats tasted a preferred sweet taste solution (0.125% saccharin +3% glucose) than after they tasted water. They were markedly lower after rats tasted a non-preferred solution-either a bitter solution (0.15% quinine hydrochloride) or a sweet solution that had previously been the conditioned stimulus for lithium-induced taste aversion. The distribution of 14C-triolein mixed with the gastric load was determined at 4 h postinfusion. Rats that received a non-preferred bitter taste had significantly more 14C remaining in the stomach than did those that received a preferred sweet taste. These results suggest that taste hedonics--either unconditioned or conditioned aversive tastes--influence fat disposition by altering gastric emptying.

Objective: The hybrid gamma camera (HGC) has been developed to enhance the localization of radiopharmaceutical uptake in targeted tissues during surgical procedures such as sentinel lymph node (SLN) biopsy. To assess the capability of the HGC, a lymph node contrast (LNC) phantom was constructed to simulate medical scenarios of varying radioactivity concentrations and SLN size. Methods: The phantom was constructed using two clear acrylic glass plates. The SLNs were simulated by circular wells of diameters ranging from 10 to 2.5 mm (16 wells in total) in 1 plate. The second plate contains four larger rectangular wells to simulate tissue background activity surrounding the SLNs. The activity used to simulate each SLN ranged between 4 and 0.025 MBq. The activity concentration ratio between the background and the activity injected in the SLNs was 1 : 10. The LNC phantom was placed at different depths of scattering material ranging between 5 and 40 mm. The collimator-to-source distance was 120 mm. Image acquisition times ranged from 60 to 240 s. Results: Contrast-to-noise ratio analysis and full-width-at-half-maximum (FWHM) measurements of the simulated SLNs were carried out for the images obtained. Over the range of activities used, the HGC detected between 87.5 and 100% of the SLNs through 20 mm of scattering material and 75–93.75% of the SLNs through 40 mm of scattering material. The FWHM of the detected SLNs ranged between 11.93 and 14.70 mm. Conclusion: The HGC is capable of detecting low accumulation of activity in small SLNs, indicating its usefulness as an intraoperative imaging system during surgical SLN procedures. Advances in knowledge: This study investigates the capability of a novel small-field-of-view (SFOV) HGC to detect low activity uptake in small SLNs. The phantom and procedure described are inexpensive and could be easily replicated and applied to any SFOV camera, to provide a comparison between systems with clinically relevant results.

We have fabricated and characterised unpassivated 200 μm diameter circular mesa Al0.8Ga0.2As p+–i–n+ diodes as soft X-ray photon counting detectors. The spectroscopic performance, as measured by the FWHM of the 5.9 keV X-ray line from an 55Fe radioisotope, shows that these detectors can be used for X-ray photon counting spectroscopy with promising energy resolution (0.9–2.5 keV) over a −30 to +90 °C temperature range.

An experiment was conducted using the InnovITS proving ground in Nuneaton. Thirty cars with volunteer drivers were asked to drive around a tight closed road circuit causing them to pass repeatedly through a cross-roads junction from all directions. The junction was signalized. In different test-runs of the experiment the traffic lights were controlled by either an automated fixed-time system or by a human using remote control. All vehicles in the test were instrumented using GPS and bluetooth. Video footage from two cameras was also recorded.recorded. The goal of the experiment was to collect data on the performance of human junction controllers. This was motivated by earlier work indicated that human controllers could perform well at this task in a simulated `computer game' environment. In particular this paper examines some of the issues that arise when trying to simulate an urban road junction in this manner. For example results are presented indicating differences in network performance depending on whether the drivers were instructed to follow a fixed route or a random route of their choice. Thus providing some guidance for maximizing the fidelity of this type of simulation in the future. The paper also presents a detailed analysis of the sensor data and video footage to measure the performance of the junction under the different modes of control.

A michrochannel plate detector has been used to image tritium-labeled protein on one- and two-dimensional electrophoresis gels. The good spatial resolution (70 microns) and high sensitivity (6.0 dpm/mm2) of the imaging system allows detection of low levels (femto moles) of labelled proteins. We are currently using the detector for identification of new targets involved in organophosphate neurotoxicity.

Superfund sites frequently contain both heavy metals and organic hazardous waste. If not properly controlled, the metals may be changed to a more leachable form and may also be emitted to the atmosphere via the exhaust stack. This paper documents a batch kiln R&D test program to solve these metal-related problems. It was performed under the U.S. EPA’s SITE (Superfund Innovative Technology Evaluation) Emerging Technology Program. Allis Mineral Systems has developed the Thermal Encapsulation Process. Metals with limits set by EPA’s TCLP (Toxicity Characteristic Leaching Procedure) test and BIF (boiler and industrial furnace) stack emission regulations, such as cadmium, chromium, and lead, are the initial target of this process. This process, while unproven in these areas, may also apply to mixed waste (EPA hazardous waste/low-level radioactive wastes) and may also benefit commercial hazardous waste or Superfund thermal treatment systems. The results of the SITE tests were positive: strong, durable ...

Organophosphorus (OP) compounds are a diverse chemical group that includes nerve agents and pesticides. They share a common chemical signature that facilitates their binding and adduction of acetylcholinesterase (AChE) within nerve synapses to induce cholinergic toxicity. However, this group diversity results in non-uniform binding and inactivation of other secondary protein targets, some of which may be adducted and protein activity influenced, even when only a relatively minor portion of tissue AChE is inhibited. The determination of individual OP protein binding targets has been hampered by the sensitivity of methods of detection and quantification of protein-pesticide adducts. We have overcome this limitation by the employment of a microchannel plate (MCP) autoradiographic detector to monitor a radiolabelled OP tracer compound. We preincubated rat thymus tissue in vitro with the OP pesticides, azamethiphos-oxon, chlorfenvinphos-oxon, chlorpyrifos-oxon, diazinon-oxon, and malaoxon, and then subsequently radiolabelled the free OP binding sites remaining with 3H-diisopropylfluorophosphate (3H-DFP). Proteins adducted by OP pesticides were detected as a reduction in 3H-DFP radiolabelling after protein separation by one dimensional polyacrylamide gel electrophoresis and quantitative digital autoradiography using the MCP imager. Thymus tissue proteins of molecular weights ~28 kDa, 59 kDa, 66 kDa, and 82 kDa displayed responsiveness to adduction by this panel of pesticides. The 59 kDa protein target (previously putatively identified as carboxylesterase I) was only significantly adducted by chlorfenvinphos-oxon (p < 0.001), chlorpyrifos-oxon (p < 0.0001), and diazinon-oxon (p < 0.01), the 66 kDa protein target (previously identified as serum albumin) similarly only adducted by the same three pesticides (p < 0.0001), (p < 0.001), and (p < 0.01), and the 82 kDa protein target (previously identified as acyl peptide hydrolase) only adducted by chlorpyrifos-oxon (p < 0.0001) and diazinon-oxon (p < 0.001), when the average values of tissue AChE inhibition were 30%, 35%, and 32% respectively. The ~28 kDa protein target was shown to be heterogeneous in nature and was resolved to reveal nineteen 3H-DFP radiolabelled protein spots by two dimensional polyacrylamide gel electrophoresis and MCP autoradiography. Some of these 3H-DFP proteins spots were responsive to adduction by preincubation with chlorfenvinphos-oxon. In addition, we exploited the useful spatial resolution of the MCP imager (~70 mm) to determine pesticide micolocalisation in vivo, after animal dosing and autoradiography of brain tissue sections. Collectively, MCP autoradiographic imaging provided a means to detect targets of OP pesticides, quantify their sensitivity of adduction relative to tissue AChE inhibition, and highlighted that these common pesticides exhibit specific binding character to protein targets, and therefore their toxicity will need to be evaluated on an individual compound basis. In addition, MCP autoradiography afforded a useful method of visualisation of the localisation of a small radiolabelled tracer within brain tissue.

A study of leakage currents and X-ray photon counting using GaAs p-i-n diodes is presented. Different fabrication techniques have been investigated, namely He implantation, partial wet etching and full wet etching. It was found that the partially etched diodes showed well-defined spectral peaks when exposed to a 55Fe radioisotope source and uniformly low leakage currents ideal for X-ray detector arrays.

Realistic Monte Carlo simulations have been performed to study the direct effect of avalanche gain distribution on the energy resolution of X-ray APDs. The dependence of the gain distribution on the incident photon energy, detector material pair creation energy, ionization coefficient ratio, dead space, position of charge injection and the mean gain itself are analyzed. The results suggest that the distribution of avalanche gain narrows significantly when the number of carriers generated per photon increases. Initiation of the impact ionization process with carriers' with the higher ionization coefficient as well as the presence of dead space were also found to narrow avalanche gain distribution.

We report on the performance of avalanche photodiodes (APDs) based on the wide band gap material AlGaAs which have been developed for soft X-ray spectroscopy applications. A number of diode types with different layer thicknesses have been characterised. The temperature dependence of the avalanche multiplication process at soft X-ray energies in Al 0.8 Ga 0.2 As APDs was investigated at temperatures from +80 °C to −20 °C. X-ray spectra from a 55Fe radioactive source show these diodes can be used for spectroscopy with promising energy resolution (0.9–2.5keV) over a wide temperature range. The temperature dependence of the pure electron initiated multiplication factor (M e ) and the mixed carrier initiated avalanche multiplication factor (M mix ) were experimentally measured. The experimental results are compared with a spectroscopic Monte Carlo model for Al 0.8 Ga 0.2 As diodes from which the temperature dependence of the pure hole initiated multiplication factor (M h ) is determined.

In today’s difficult economic climate, business managers must carefully consider all aspects of business operations to minimize waste and increase efficiency. The revenue cycle continues to be the primary area of fraud and abuse requiring strong, comprehensive internal controls (AICPA 2002). Internal controls in the revenue arena are now more important than ever. The current paper provides a control review checklist for the revenue cycle that will aid managers and independent auditors in the consumer products industry. The checklist is applicable for firms at various levels of the distribution channel and can be used as a general benchmark to perform preliminary evaluations of a company’s internal control system. Auditors can compare their company’s control objectives with the objectives that are presented. During preliminary investigations of the company’s internal control system, auditors should review whether important control objectives have been omitted and whether the omission incurs or heightens risk. The control review checklist can also be used by CFOs or Controllers in the Consumer Products industry in reviewing whether their company’s internal control systems are adequate. The checklist provides CFOs or Controllers internal controls that external, independent auditors consider to be important.

An extensive study of the structural and morphological properties of the dispersion of iron(III) ions in titanium dioxide has revealed that well dispersed biphasic solids (Fe3+ ions dispersed into the lattice of both modifications of TiO2, anatase and rutile) are formed with co-precipitated solids which nominally contain 0.5 and 1.0 atom% of iron. Heavily iron-loaded ( >5%) solids become multi-phasic at 923 K and above, with the production of α-Fe2O3 at the lower segregation temperature (923 K) and Fe2TiO5 at the highest temperatures (1073 and 1273 K) from a reaction between the segregated α-Fe2O3 and the saturated iron-doped titanium dioxide. Magnetic susceptibility studies of the solids confirm that a good degree of dispersion of iron exists in the co-precipitated solids at 0.5 and 1.0% iron loadings (Curie law behaviour), and that stronger magnetic interactions (Curie–Weiss law behaviour) arise in heavily loaded specimens that have been fired at the highest temperatures (1273 K). At lower temperatures, two unusual phenomena have been observed with specimens that have been loaded heavily (5%) by impregnation. At 773 K the temperature dependence of χg produces a ‘double slope’ Curie–Weiss plot owing to the formation of an incipient haematite layer on the surface of the TiO2 particles, while at 923 K this solid produces antiferromagnetic behaviour owing to the appearance of α-Fe2O3. The transition from Curie behaviour to Curie–Weiss behaviour occurs in the region of nominal iron concentration between 1 and 2 atom%, which is below the estimated solubility limit of ca. 3 atom% of Fe3+ in the rutile phase at 923 K.

Personal Rapid Transit (PRT) systems are designed so that passengers usually travel together only by choice, but strangers may choose to share a vehicle at peak times, when the system is near capacity. By predicting whether and to what extent this ride sharing will occur, PRT planners can better estimate the impact on system capacity and passenger experience. This paper develops a model for ride sharing based on queueing theory and applies it to explain the relationships between vehicle occupancy, passenger queue length and passenger waiting time. The effects of multiple destinations, passengers who are unwilling to share and passengers arriving in preformed parties are considered. A case study is provided to show how the model can be applied to a simple point-to-point system; in this case study it appears possible to reduce the size of the vehicle fleet by at least 30%, while still maintaining a high level of service for passengers during peak times.

We explore several ways to estimate movie similarity from the free encyclopedia Wikipedia with the goal of improving our predictions for the Netflix Prize. Our system first uses the content and hyperlink structure of Wikipedia articles to identify similarities between movies. We then predict a user's unknown ratings by using these similarities in conjunction with the user's known ratings to initialize matrix factorization and k-Nearest Neighbours algorithms. We blend these results with existing ratings-based predictors. Finally, we discuss our empirical results, which suggest that external Wikipedia data does not significantly improve the overall prediction accuracy.