| 1. |
- Sun, Aijun, 1973-
(author)
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Radiolabeled acetate PET in oncology imaging : studies on head and neck cancer, prostate cancer and normal distribution
- 2010
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Doctoral thesis (other academic/artistic)abstract
- The use of positron emission tomography (PET) for imaging in oncology has grown rapidly in recent years. 2-[18F]-fluorodeoxyglucose (FDG) is the most common tracer of PET, although drawbacks exist. Radiolabeled 1-[11C]-acetate (C-AC) is a simple probe for evaluation of perfusion, anabolism (lipogenesis) and catabolism (oxidative metabolism) in all living tissues. This study explored the potential of AC PET in head and neck cancer, benign and malignant lymph nodes in prostate cancer and normal distribution. In head and neck cancer, C-AC PET detected more primaries and lymph node metastases than FDG PET. The mean primary tumor volumes delineated by C-AC was 51% larger than that of FDG before radiotherapy (RT). Both FDG and C-AC PET tumor volumes must be carefully validated before used in clinical routine. Baseline tumor clearance rate (kmono) was higher in complete responders (CR) than that in partial responders (PR). kmono tended to correlate inversely with FDG SUV at baseline. Radiosensitive tumors might rely predominantly on oxidative metabolism for their biogenetic needs. kmono increased in PR during RT. The potential reversibility of impaired kmono in radioresistant tumors imply that treatment targeting the intermediary metabolism might improve the outcome. Tumor relative perfusion index (rF) and kmono were coupled in CR throughout the RT, but not in PR. Dynamic C-AC PET provides a new non-invasive method to simultaneously evaluate the tumor oxidative metabolism and perfusion which link the RT response in patients by a single tracer injection. In prostate cancer, elevated C-AC accumulation is common in benign inguinal lymph nodes, probably due to increased lipogenesis rather than lymphatic drainage. CT Hounsfield unit of benign nodes was lower than that of metastases, suggesting that density measurement using CT might improve the specificity of nodal staging of prostate cancer. A novel tracer 2-[18F]-fluoroacetate (F-AC) was synthesized and used for dynamic PET-CT imaging in animals. Compared with C-AC PET-CT, F-AC showed prolonged blood retention, no detectable trapping in myocardium and salivary glands, rapid excretion from liver to bile and urine and de-fluorination resulting in intensive skeletal activity. F-AC does not mimic the normal physiologic path of C-AC and appears to be of little use for assessment of perfusion, intermediary metabolism or lipogenesis.
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| 2. |
- Garpebring, Anders, 1980-
(author)
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Contributions to quantitative dynamic contrast-enhanced MRI
- 2011
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Doctoral thesis (other academic/artistic)abstract
- Background: Dynamic contrast-enhanced MRI (DCE-MRI) has the potential to produce images of physiological quantities such as blood flow, blood vessel volume fraction, and blood vessel permeability. Such information is highly valuable, e.g., in oncology. The focus of this work was to improve the quantitative aspects of DCE-MRI in terms of better understanding of error sources and their effect on estimated physiological quantities. Methods: Firstly, a novel parameter estimation algorithm was developed to overcome a problem with sensitivity to the initial guess in parameter estimation with a specific pharmacokinetic model. Secondly, the accuracy of the arterial input function (AIF), i.e., the estimated arterial blood contrast agent concentration, was evaluated in a phantom environment for a standard magnitude-based AIF method commonly used in vivo. The accuracy was also evaluated in vivo for a phase-based method that has previously shown very promising results in phantoms and in animal studies. Finally, a method was developed for estimation of uncertainties in the estimated physiological quantities. Results: The new parameter estimation algorithm enabled significantly faster parameter estimation, thus making it more feasible to obtain blood flow and permeability maps from a DCE-MRI study. The evaluation of the AIF measurements revealed that inflow effects and non-ideal radiofrequency spoiling seriously degrade magnitude-based AIFs and that proper slice placement and improved signal models can reduce this effect. It was also shown that phase-based AIFs can be a feasible alternative provided that the observed difficulties in quantifying low concentrations can be resolved. The uncertainty estimation method was able to accurately quantify how a variety of different errors propagate to uncertainty in the estimated physiological quantities. Conclusion: This work contributes to a better understanding of parameter estimation and AIF quantification in DCE-MRI. The proposed uncertainty estimation method can be used to efficiently calculate uncertainties in the parametric maps obtained in DCE-MRI.
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| 3. |
- Häggström, Ida, 1982-
(author)
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Quantitative methods for tumor imaging with dynamic PET
- 2014
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Doctoral thesis (other academic/artistic)abstract
- There is always a need and drive to improve modern cancer care. Dynamic positron emission tomography (PET) offers the advantage of in vivo functional imaging, combined with the ability to follow the physiological processes over time. In addition, by applying tracer kinetic modeling to the dynamic PET data, thus estimating pharmacokinetic parameters associated to e.g. glucose metabolism, cell proliferation etc., more information about the tissue's underlying biology and physiology can be determined. This supplementary information can potentially be a considerable aid when it comes to the segmentation, diagnosis, staging, treatment planning, early treatment response monitoring and follow-up of cancerous tumors.We have found it feasible to use kinetic parameters for semi-automatic tumor segmentation, and found parametric images to have higher contrast compared to static PET uptake images. There are however many possible sources of errors and uncertainties in kinetic parameters obtained through compartment modeling of dynamic PET data. The variation in the number of detected photons caused by the random nature of radioactive decay, is of course always a major source. Other sources may include: the choice of an appropriate model that is suitable for the radiotracer in question, camera detectors and electronics, image acquisition protocol, image reconstruction algorithm with corrections (attenuation, random and scattered coincidences, detector uniformity, decay) and so on. We have found the early frame sampling scheme in dynamic PET to affect the bias and uncertainty in calculated kinetic parameters, and that scatter corrections are necessary for most but not all parameter estimates. Furthermore, analytical image reconstruction algorithms seem more suited for compartment modeling applications compared to iterative algorithms.This thesis and included papers show potential applications and tools for quantitative pharmacokinetic parameters in oncology, and help understand errors and uncertainties associated with them. The aim is to contribute to the long-term goal of enabling the use of dynamic PET and pharmacokinetic parameters for improvements of today's cancer care.
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| 4. |
- Johansson, Adam, 1984-
(author)
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Magnetic resonance imaging with ultrashort echo time as a substitute for X-ray computed tomography
- 2014
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Doctoral thesis (other academic/artistic)abstract
- Radiotherapy dose calculations have evolved from simple factor based methods performed with pen and paper, into computationally intensive simulations based on Monte Carlo theory and energy deposition kernel convolution.Similarly, in the field of positron emission tomography (PET), attenuation correction, which was originally omitted entirely, is now a crucial component of any PET reconstruction algorithm.Today, both of these applications – radiotherapy and PET – derive their needed in-tissue radiation attenuation coefficients from images acquired with X-ray computed tomography (CT). Since X-ray images are themselves acquired using ionizing radiation, the intensity at a point in an image will reflect the radiation interaction properties of the tissue located at that point.Magnetic resonance imaging (MRI), on the other hand, does not use ionizing radiation. Instead MRI make use of the net transverse magnetization resulting from the spin polarization of hydrogen nuclei. MR image contrast can be varied to a greater extent than CT and the soft tissue contrast is, for most MR sequences, superior to that of CT. Therefore, for many cases, MR images provide a considerable advantage over CT when identifying or delineating tumors or other diseased tissues.For this reason, there is an interest to replace CT with MRI for a great number of diagnostic and therapeutic workflows. Also, replacing CT with MRI would reduce the exposure to ionizing radiation experienced by patients and, by extension, reduce the associated risk to induce cancer.In part MRI has already replaced CT, but for radiotherapy dose calculations and PET attenuation correction, CT examinations are still necessary in clinical practice. One of the reasons is that the net transverse magnetization imaged in MRI cannot be converted into attenuation coefficients for ionizing radiation in a straightforward way. More specifically, regions with similar appearance in magnetic resonance (MR) images, such as bone and air pockets, are found at different ends of the spectrum of attenuation coefficients present in the human body. In a CT image, bone will appear bright white and air as black corresponding to high and no attenuation, respectively. In an MR image, bone and air both appear dark due to the lack of net transverse magnetization.The weak net transverse magnetization of bone is a result of low hydrogen density and rapid transverse relaxation. A particular category of MRI sequences with so-called ultrashort echo time (UTE) can sample the MRI signal from bone before it is lost due to transverse relaxation. Thus, UTE sequences permit bone to be imaged with MRI albeit with weak intensity and poor resolution.Imaging with UTE in combination with careful image analysis can permit ionizing-radiation attenuation-maps to be derived from MR images. This dissertation and appended articles present a procedure for this very purpose. However, as attenuation coefficients are radiation-quality dependent the output of the method is a Hounsfield unit map, i.e. a substitute for a CT image. It can be converted into an attenuation map using conventional clinical procedure.Obviating the use of CT would reduce the number of examinations that patients have to endure during preparation for radiotherapy. It would also permit PET attenuation correction to be performed on images from the new imaging modality that combines PET and MRI in one scanner – PET/MR.
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| 5. |
- Jonsson, Joakim, 1984-
(author)
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Integration of MRI into the radiotherapy workflow
- 2013
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Doctoral thesis (other academic/artistic)abstract
- The modern day radiotherapy treatments are almost exclusively based on computed tomography (CT) images. The CT images are acquired using x-rays, and therefore reflect the radiation interaction properties of the material. This information is used to perform accurate dose calculation by the treatment planning system, and the data is also well suited for creating digitally reconstructed radiographs for comparing patient set up at the treatment machine where x-ray images are routinely acquired for this purpose.The magnetic resonance (MR) scanner has many attractive features for radiotherapy purposes. The soft tissue contrast as compared to CT is far superior, and it is possible to vary the sequences in order to visualize different anatomical and physiological properties of an organ. Both of these properties may contribute to an increase in accuracy of radiotherapy treatment.Using the MR images by themselves for treatment planning is, however, problematic. MR data reflects the magnetic properties of protons, and thus have no connection to the radiointeraction properties of the material. MRI also has inherent difficulty in imaging bone, which will appear in images as areas of no signal similar to air. This makes both dose calculation and patient positioning at the treatment machine troublesome.There are several clinics that use MR images together with CT images to perform treatment planning. The images are registered to a common coordinate system, a process often described as image fusion. In these cases, the MR images are primarily used for target definition and the CT images are used for dose calculations. This method is now not ideal, however, since the image fusion may introduce systematic uncertainties into the treatment due to the fact that the tumor is often able to move relatively freely with respect to the patients’ bony anatomy and outer contour, especially when the image registration algorithms take the entire patient anatomy in the volume of interest into account.The work presented in the thesis “Integration of MRI into the radiotherapy workflow” aim towards investigating the possibilities of workflows based entirely on MRI without using image registration, as well as workflows using image registration methods that are better suited for targets that can move with respect to surrounding bony anatomy, such as the prostate.
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| 6. |
- Karlsson, Mikael, 1972-
(author)
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Filantropi under konstruktion : En undersökning av Sällskapet DBW:s samhällsengagemang 1814–1876
- 2012
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Doctoral thesis (other academic/artistic)abstract
- The 19th century was a time when a large number of voluntary associations were being formed both in Sweden and in Europe as a whole. Their ambition was to engage in health care and poor relief issues as well as in the educational system. Furthermore, the general idea was to promote temperance and foster a sense of thrift among the poor and the working class population.While the starting-point of the thesis was the question as to why the voluntary associations founded various charitable activities as well as how the philanthropy was designed, organised and modified throughout the century, the aim has been to elucidate the motive force and incentives for their social reforms. In order to answer the two main questions of the dissertation, the association De Badande Wännerna (the DBW), which engaged in several philanthropic activities in the Swedish province of Gotland as early as the 1810s, has been selected for a case study.In the literature a number of different reasons have been stressed as to why voluntary associations chose to engage in charitable activities. In order to shed light on what factors that underlay their philanthropic work, the process of negotiation regarding the various institutions established by the DBW, as well as the practical layout of the establishments, have been analysed from the perspectives of a theoretical model based on affinity groups.The study has shown that the incentives of philanthropy were complex. Furthermore, the incentives changed concurrently with the expansion of the public poor relief and educational system, which from the middle of the 19th century took over many of the humanitarian efforts hitherto run by the voluntary associations. The result of this development was that the voluntary associations created new spheres of activity. They continued to fulfil important societal functions, but their establishments also fulfilled a more internal desire for pleasure and delights.
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| 7. |
- Karlsson, Olof Magnus, 1972-
(author)
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Predicting Ecosystem Response from Pollution in Baltic Archipelago areas using Mass-balance Modelling
- 2011
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Doctoral thesis (other academic/artistic)abstract
- Baltic archipelago areas have high nature values despite being polluted from various antrophogenic activities within the Baltic Sea catchment area and from long-range transport of airborne substances. The discovery of environmental problems in the Baltic Sea in the 1960s led to countermeasures that gradually gave results in reducing the toxic pollution, e.g. from PCBs. Today, much of the environmental management is focused on reducing the effects of eutrophication. There is a demand from society on science to develop strategies that can direct remedial actions so that the cost-effectiveness is maximised. This work focuses on how mass-balance models can be used to understand how coastal ecosystems are controlled by abiotic processes and to predict the response to changes in loading of different substances. Advection, sedimentation and burial are examples of general transport processes that are regulated by morphometrical characteristics, e.g. size, form, effective fetch and topographical openness. This is why different coastal areas have different sensitivity to loading of pollutants. A comparison of six phosphorus and chlorophyll models of different complexity showed that the model performance was not improved with more state variables of total phosphorus (TP) than two water and two sediment compartments. Modelling chlorophyll as a separate state variable did not improve the results for individual values compared to a simple regression against total phosphorus in surface water. Field investigations of the phosphorus content in accumulation sediments along the coast of Svealand showed a distribution pattern that probably is related to differences in the redox status. The average content of mobile phosphorus was much higher than previously found in offshore Baltic sediments indicating that sediments may play an important role for the phosphorus turnover in Baltic archipelago areas. A one-year field study to measure the levels of polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs) in water, sediments and fish during different seasons was carried out in Kallrigafjärden Bay. The collected data set was used to test a mass-balance model for PCCD/F-turnover. It was possible to reproduce the concentrations of different PCDD/F-congeners with high accuracy using a general model approach, including one water compartment and two sediment compartments, indicating that the applied model has the necessary qualifications for successful predictions of PCDD/F-turnover in Baltic coastal areas.
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| 8. |
- Karlsson, Terese, 1979-
(author)
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The expression and molecular functions of LRIG proteins in cancer and psoriasis
- 2013
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Doctoral thesis (other academic/artistic)abstract
- The leucine-rich repeats and immunoglobulin-like domains (LRIG) family consists of three integral membrane proteins that are important in human cancer. LRIG1 is a negative regulator of growth factor signaling. Its expression is associated with longer survival in several cancer types, and the gene has been shown to function as a tumor suppressor. The roles of LRIG2 and LRIG3 are less well known. The aim of this thesis was to improve our understanding of the expression and function of the LRIG protein family in psoriasis and cancer.To investigate their expression in psoriasis, the mRNA levels and subcellular localization of the LRIG proteins were analyzed and compared between normal and psoriatic human skin. There were no differences in the LRIG mRNA levels between psoriatic and normal skin samples. However, the subcellular localization of all three LRIG proteins differed between psoriatic and normal skin.To study the physiological and molecular functions of Lrig2, we generated Lrig2E12-/- mice. These mice were viable and born at a Mendelian rate, but Lrig2E12-/- mice had an increased rate of spontaneous mortality and a transient reduction in growth rate compared to Lrig2 wild-type (wt) mice. In an orthotopic platelet-derived growth factor (PDGF)B-driven brain tumor mouse model, we studied the effect of Lrig2 on gliomagenesis. All Lrig2 wt mice developed tumors; 82% developed grade II/III tumors, and 18% developed grade IV tumors. Only 77% of the Lrig2E12-/- mice developed tumors, and they were all grade II/III tumors. Thus, Lrig2 increased the incidence and malignancy rates of PDGFB-driven gliomas. We then analyzed the effect of Lrig2 on Pdgf receptor (Pdgfr) signaling. Lrig2 had no effect on Pdgfr steady-state levels, the starvation-induced up-regulation of Pdgfrs, the phosphorylation of Pdgfrs, primary cilium formation or the PDGFBB-induced phosphorylation of Akt or Erk1/2. However, the kinetics of induction of the immediate-early genes Fos and Egr2 were altered, resulting in a more rapid induction in Lrig2E12-/- cells.We then analyzed the clinical and biological importance of LRIG1 in lung cancer. In a human lung cancer tissue micro-array (TMA), LRIG1 expression was found to be an independent positive prognostic factor for adenocarcinoma. To study the importance of Lrig1 regarding lung cancer development in vivo, we used an inducible EGFRL858R-driven mouse lung cancer model. The mice developed diffuse lung adenocarcinoma, and the tumor burden was greater in Lrig1-/- mice than in Lrig1+/+ mice (p = 0.025) at 60 days. The human lung cancer cell line H1975, with either normal or Tet-induced expression of LRIG1, was injected into the flanks of Balb/cA nude mice. Tumors formed by LRIG1-overexpressing cells were smaller than those formed by parental cells, further indicating that LRIG1 is important during lung tumor formation or growth. In vitro, LRIG1 suppressed the proliferation of H1975 cells and down-regulated the phosphorylation of MET and RET.To investigate the molecular functions of LRIG proteins further, we performed a yeast two-hybrid (YTH) screen using a peptide from the cytosolic tail of LRIG3 as bait. This screen identified LMO7 and LIMCH1 as prominent interaction partners for LRIG3. Proximity ligation assays showed that LMO7 interacted with all of the LRIG proteins at endogenous expression levels. LMO7 and LIMCH1 were expressed in all human tissues analyzed. Their expression was dramatically decreased in lung cancer compared to normal lung tissue. The expression of LMO7 was analyzed in a human lung cancer TMA. LMO7 was expressed in respiratory epithelial cells in normal lungs. However, LMO7 was only expressed in a quarter of the lung tumors. LMO7 expression was found to be an independent negative prognostic factor for lung cancer.In summary, we found that the LRIG proteins were redistributed in psoriatic skin. In a mouse glioma model, Lrig2 promoted oligodendroglioma genesis. LRIG1 was an independent positive prognostic factor in human lung cancer. Lrig1 ablation increased the tumor size in an EGFRL858R-driven lung cancer mouse model. LRIG1 expression decreased the tumor growth of human lung cancer cells in a xenograft mouse model. LMO7 interacted with all three LRIG proteins and was an independent negative prognostic factor in human lung cancer. These data demonstrate the importance of LRIG proteins in human disease.
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| 9. |
- Forsberg, Pontus, 1981-
(author)
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Diamond Microfabrication for Applications in Optics and Chemical Sensing
- 2013
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Doctoral thesis (other academic/artistic)abstract
- Diamond is a material with many exceptional properties. In this thesis methods for fabrication of microstructures as well as several applications of such structures in optics, microfluidics and electrochemistry are presented.A method for etching deep and highly precise gratings is described. This method was used to fabricate circularly symmetric half wave plates for use in vector vortex coronagraphs. Such coronagraphs are a very promising approach to the direct imaging of extrasolar planets.By varying the lateral etch rate of the aluminum mask during diamond etching in an inductively coupled plasma, the sidewall angle of the etched structures could be controlled. This method was used to make smooth sloped sides on a waveguide for coupling light into it. Antireflective structures that drastically reduced the surface reflection in a wavelength band between 10 and 50 µm were also fabricated.An array of boron doped diamond microelectrodes for electrochemical measurements in a microchannel was fabricated and tested, showing very good stability and reusability. Several hundred hours of use did not adversely affect their performance and no damage to them could be detected by atomic force microscopy or scanning electron microscopy.Superhydrophobic surfaces in diamond were demonstrated, using both hydrogen and fluorine termination. Hydrogen termination on a flat surface gives contact angles below 90°. To achieve a superhydrophobic surface with this low intrinsic hydrophobicity, structures looking like microscopic nail heads were fabricated. The effect of water pressure on immersed superhydrophobic surfaces was also studied and it was found that the collapse of the superhydrophobic state due to pressure was sometimes reversible as the pressure was lowered.Finally, a method was tested for functionalizing diamond surfaces using block copolymers of polyethylene oxide and polypropylene oxide to both passivate the surface and to attach synthetic binder molecules. This method was found to give very high signal to noise ratios when detecting C-reactive protein.
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| 10. |
- Karlsson, Mikael
(author)
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Aeroacoustics Studies of Duct Branches with Application to Silencers
- 2010
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Doctoral thesis (other academic/artistic)abstract
- New methodologies and concepts for developing compact and energy efficient automotive exhaust systems have been studied. This originates in the growing concern for global warming, to which road transportation is a major contributor. The focus has been on commercial vehicles—most often powered by diesel engines—for which the emission legislation has been dramatically increased over the last decade. The emissions of particulates and nitrogen oxides have been successfully reduced by the introduction of filters and catalytic converters, but the fuel consumption, which basically determines the emissions of carbon dioxides, has not been improved accordingly. The potential reduction of fuel consumption by optimising the exhaust after-treatment system (assuming fixed after-treatment components) of a typical heavy-duty commercial vehicle is ~4%, which would have a significant impact on both the environment and the overall economy of the vehicle.First, methodologies to efficiently model complex flow duct networks such as exhaust systems are investigated. The well-established linear multiport approach is extended to include flow-acoustic interaction effects. This introduces an effective way of quantifying amplification and attenuation of incident sound, and, perhaps more importantly, the possibility of predicting nonlinear phenomena such as self-sustained oscillations—whistling—using linear models. The methodology is demonstrated on T-junctions, which is a configuration well known to be prone to self-sustained oscillations for grazing flow past the side branch orifice. It is shown, and validated experimentally, that the existence and frequency of self-sustained oscillations can be predicted using linear theory.Further, the aeroacoustics of T-junctions are studied. A test rig for the full determination of the scattering matrix defining the linear three-port representing the T-junction is developed, allowing for any combination of grazing-bias flow. It is shown that the constructive flow-acoustic coupling not only varies with the flow configuration but also with the incidence of the acoustic disturbance. Configurations where flow from the side branch joins the grazing flow are still prone to whistling, while flow bleeding off from the main branch effectively cancels any constructive flow-acoustic coupling.Two silencer concepts are evaluated: first the classic Herschel-Quincke tube and second a novel modified flow reversal silencer. The Herschel-Quincke tube is capable of providing effective attenuation with very low pressure loss penalty. The attenuation conditions are derived and their sensitivity to mean flow explained. Two implementations have been modelled using the multiport methodology and then validated experimentally. The first configuration, where the nodal points are composed of T-junctions, proves to be an example where internal reflections in the system can provide sufficient feedback for self-sustained oscillation. Again, this is predicted accurately by the linear theory. The second implementation, with nodal points made from Y-junctions, was designed to allow for equal flow distribution between the two parallel ducts, thus allowing for the demonstration of the passive properties of the system. Experimental results presented for these two configurations correlate well with the derived theory.The second silencer concept studied consists of a flow reversal chamber that is converted to a resonator by acoustically short-circuiting the inlet and outlet ducts. The eigenfrequency of the resonator is easily shifted by varying the geometry of the short circuit, thus making the proposed concept ideal for implementation as a semi-active device. Again the concept is modelled using the multiport approach and validated experimentally. It is shown to provide significant attenuation over a wide frequency range with a very compact design, while adding little or no pressure loss to the system.
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