Improved correction for the tissue fraction effect in lung PET/CT imaging

Recently, there has been an increased interest in imaging different pulmonary disorders using PET techniques. Previous work has shown, for static PET/CT, that air content in the lung influences reconstructed image values and that it is vital to correct for this 'tissue fraction effect' (TFE). In this paper, we extend this work to include the blood component and also investigate the TFE in dynamic imaging. CT imaging and PET kinetic modelling are used to determine fractional air and blood voxel volumes in six patients with idiopathic pulmonary fibrosis. These values are used to illustrate best and worst case scenarios when interpreting images without correcting for the TFE. In addition, the fractional volumes were used to determine correction factors for the SUV and the kinetic parameters. These were then applied to the patient images. The kinetic parameters K1 and Ki along with the static parameter SUV were all found to be affected by the TFE with both air and blood providing a significant contribution to the errors. Without corrections, errors range from 34-80% in the best case and 29-96% in the worst case. In the patient data, without correcting for the TFE, regions of high density (fibrosis) appeared to have a higher uptake than lower density (normal appearing tissue), however this was reversed after air and blood correction. The proposed correction methods are vital for quantitative and relative accuracy. Without these corrections, images may be misinterpreted

A novel protein isoform of the RON tyrosine kinase receptor transforms human pancreatic duct epithelial cells.

The MST1R gene is overexpressed in pancreatic cancer producing elevated levels of the RON tyrosine kinase receptor protein. While mutations in MST1R are rare, alternative splice variants have been previously reported in epithelial cancers. We report the discovery of a novel RON isoform discovered in human pancreatic cancer. Partial splicing of exons 5 and 6 (P5P6) produces a RON isoform that lacks the first extracellular immunoglobulin-plexin-transcription domain. The splice variant is detected in 73% of xenografts derived from pancreatic adenocarcinoma patients and 71% of pancreatic cancer cell lines. Peptides specific to RON P5P6 detected in human pancreatic cancer specimens by mass spectrometry confirm translation of the protein isoform. The P5P6 isoform is found to be constitutively phosphorylated, present in the cytoplasm, and it traffics to the plasma membrane. Expression of P5P6 in immortalized human pancreatic duct epithelial (HPDE) cells activates downstream AKT, and in human pancreatic epithelial nestin-expressing cells, activates both the AKT and MAPK pathways. Inhibiting RON P5P6 in HPDE cells using a small molecule inhibitor BMS-777607 blocked constitutive activation and decreased AKT signaling. P5P6 transforms NIH3T3 cells and induces tumorigenicity in HPDE cells. Resultant HPDE-P5P6 tumors develop a dense stromal compartment similar to that seen in pancreatic cancer. In summary, we have identified a novel and constitutively active isoform of the RON tyrosine kinase receptor that has transforming activity and is expressed in human pancreatic cancer. These findings provide additional insight into the biology of the RON receptor in pancreatic cancer and are clinically relevant to the study of RON as a potential therapeutic target

Density variation during respiration affects PET quantitation in the lung

PET quantitation depends on the accuracy of the CT-derived attenuation correction map. In the lung, respiration leads to both positional and density mismatches, causing PET quantitation errors at lung borders but also within the whole lung. The aim of this work is to determine the extent of the associated errors on the measured time activity curves (TACs) and the corresponding kinetic parameter estimates. 5 patients with idiopathic pulmonary fibrosis underwent dynamic 18 F-FDG PET and cine-CT imaging as part of an ongoing study. The cine-CT was amplitude gated using PCA techniques to produce end expiration (EXP), end inspiration (INS) and mid-breathing cycle (MID) gates representative of a short clinical CT acquisition. The ungated PET data were reconstructed with each CT gate and the TACs and kinetic parameters compared. Patient representative XCAT simulations with varying lung density, both with and without motion, were also produced to represent the above study allowing comparison of true to measured results. In all cases, the obtained PET TACs differed with each CT gate. For ROIs internal to the lung, the effect was dominated by changes in density, as opposed to motion. The errors in the TACs varied with time, providing evidence that errors due to attenuation mismatch depend on activity distribution. In the simulations, some kinetic parameters were over- and under-estimated by a factor of 2 in the INS and EXP gates respectively. For the patients, the maximum variation in kinetic parameters was 20%. Our results show that whole lung density changes during the respiratory cycle have a significant impact on PET quantitation. This is especially true of the kinetic parameter estimates as the extent of the error is dependent on tracer distribution which varies with time. It is therefore vital to use matched PET/CT for attenuation correction

On the Perturbative Stability of Quantum Field Theories in de Sitter Space

We use a field theoretic generalization of the Wigner-Weisskopf method to study the stability of the Bunch-Davies vacuum state for a massless, conformally coupled interacting test field in de Sitter space. We find that in $\lambda \phi^4$ theory the vacuum does {\em not} decay, while in non-conformally invariant models, the vacuum decays as a consequence of a vacuum wave function renormalization that depends \emph{singularly} on (conformal) time and is proportional to the spatial volume. In a particular regularization scheme the vacuum wave function renormalization is the same as in Minkowski spacetime, but in terms of the \emph{physical volume}, which leads to an interpretation of the decay. A simple example of the impact of vacuum decay upon a non-gaussian correlation is discussed. Single particle excitations also decay into two particle states, leading to particle production that hastens the exiting of modes from the de Sitter horizon resulting in the production of \emph{entangled superhorizon pairs} with a population consistent with unitary evolution. We find a non-perturbative, self-consistent "screening" mechanism that shuts off vacuum decay asymptotically, leading to a stationary vacuum state in a manner not unlike the approach to a fixed point in the space of states.Comment: 36 pages, 4 figures. Version to appear in JHEP, more explanation

Dual equipoise shared decision making: definitions for decision and behaviour support interventions

Contains fulltext : 80919.pdf (publisher's version ) (Open Access)ABSTRACT: BACKGROUND: There is increasing interest in interventions that can support patients who face difficult decisions and individuals who need to modify their behaviour to achieve better outcomes. Evidence for effectiveness is used to categorise patients care. Effective care is where evidence of benefit outweighs harm: patients should always receive this type of care, where indicated. Preference-sensitive care describes a situation where the evidence for the superiority of one treatment over another is either not available or does not allow differentiation; in this situation, there are two or more valid approaches, and the best choice depends on how individuals value the risks and benefits of treatments. DISCUSSION: Preference-sensitive decisions are defined by equipoise: situations where options need to be deliberated. Moreover, where both healthcare professionals and patients agree that equipoise exists, situations may be regarded as having 'dual equipoise'. Such conditions are ideal for shared decision making. However, there are many situations in medicine where dual equipoise does not exist, where health professionals hold the view that scientific evidence for benefit strongly outweighs harm. This is often the case where people suffer from chronic conditions, and where behaviour change is recommended to improve outcomes. However, some patients, are either ambivalent or find it difficult to sustain optimal behaviours, i.e., patients will be in varying degrees of equipoise. Therefore, situations where dual equipoise exists (or not) help to clarify the definitions of two classes of support, namely, decision and behaviour change support interventions. Decision support interventions help people think about choices they face; they describe where and why choice exists, in short, conditions of dual equipoise; they provide information about options, including, where reasonable, the option of taking no action. These interventions help people to deliberate, independently or in collaboration with others, about options by considering relevant attributes; they support people to forecast how they might feel about short, intermediate, and long-term outcomes that have relevant consequences, in ways that help the process of constructing preferences and eventual decision making appropriate to their individual situation. Whereas, behavioural support interventions describe, justify, and recommend actions that, over time, lead to predictable outcomes over short, intermediate, and long-term timeframes, and that have relevant and important consequences for those who are considering behaviour change. SUMMARY: Decision and behaviour support interventions have divergent aims, different relationships to equipoise, and form two classes of interventions

An exploration of parents’ preferences for foot care in juvenile idiopathic arthritis: a possible role for the discrete choice experiment

Background: An increased awareness of patients’ and parents’ care preferences regarding foot care is desirable from a clinical perspective as such information may be utilised to optimise care delivery. The aim of this study was to examine parents’ preferences for, and valuations of foot care and foot-related outcomes in juvenile idiopathic arthritis (JIA).<p></p> Methods: A discrete choice experiment (DCE) incorporating willingness-to-pay (WTP) questions was conducted by surveying 42 parents of children with JIA who were enrolled in a randomised-controlled trial of multidisciplinary foot care at a single UK paediatric rheumatology outpatients department. Attributes explored were: levels of pain; mobility; ability to perform activities of daily living (ADL); waiting time; referral route; and footwear. The DCE was administered at trial baseline. DCE data were analysed using a multinomial-logit-regression model to estimate preferences and relative importance of attributes of foot care. A stated-preference WTP question was presented to estimate parents’ monetary valuation of health and service improvements.<p></p> Results: Every attribute in the DCE was statistically significant (p < 0.01) except that of cost (p = 0.118), suggesting that all attributes, except cost, have an impact on parents’ preferences for foot care for their child. The magnitudes of the coefficients indicate that the strength of preference for each attribute was (in descending order): improved ability to perform ADL, reductions in foot pain, improved mobility, improved ability to wear desired footwear, multidisciplinary foot care route, and reduced waiting time. Parents’ estimated mean annual WTP for a multidisciplinary foot care service was £1,119.05.<p></p> Conclusions: In terms of foot care service provision for children with JIA, parents appear to prefer improvements in health outcomes over non-health outcomes and service process attributes. Cost was relatively less important than other attributes suggesting that it does not appear to impact on parents’ preferences.<p></p&gt

SdrF, a Staphylococcus epidermidis Surface Protein, Contributes to the Initiation of Ventricular Assist Device Driveline–Related Infections

Staphylococcus epidermidis remains the predominant pathogen in prosthetic-device infections. Ventricular assist devices, a recently developed form of therapy for end-stage congestive heart failure, have had considerable success. However, infections, most often caused by Staphylococcus epidermidis, have limited their long-term use. The transcutaneous driveline entry site acts as a potential portal of entry for bacteria, allowing development of either localized or systemic infections. A novel in vitro binding assay using explanted drivelines obtained from patients undergoing transplantation and a heterologous lactococcal system of surface protein expression were used to identify S. epidermidis surface components involved in the pathogenesis of driveline infections. Of the four components tested, SdrF, SdrG, PIA, and GehD, SdrF was identified as the primary ligand. SdrF adherence was mediated via its B domain attaching to host collagen deposited on the surface of the driveline. Antibodies directed against SdrF reduced adherence of S. epidermidis to the drivelines. SdrF was also found to adhere with high affinity to Dacron, the hydrophobic polymeric outer surface of drivelines. Solid phase binding assays showed that SdrF was also able to adhere to other hydrophobic artificial materials such as polystyrene. A murine model of infection was developed and used to test the role of SdrF during in vivo driveline infection. SdrF alone was able to mediate bacterial adherence to implanted drivelines. Anti-SdrF antibodies reduced S. epidermidis colonization of implanted drivelines. SdrF appears to play a key role in the initiation of ventricular assist device driveline infections caused by S. epidermidis. This pluripotential adherence capacity provides a potential pathway to infection with SdrF-positive commensal staphylococci first adhering to the external Dacron-coated driveline at the transcutaneous entry site, then spreading along the collagen-coated internal portion of the driveline to establish a localized infection. This capacity may also have relevance for other prosthetic device–related infections

Challenging the perceptions of cancer service provision for the disadvantaged: evaluating utilisation of cancer support services in Western Australia

Purpose: The main aim of the study was to evaluate the distributive utilisation of services provided by the Cancer Council of Western Australia according to age, social disadvantage and geographic location. Results were used to determine if social justice principles in terms of service provision were upheld. Methods: Cross-sectional study design to evaluate utilisation of cancer support services over a 12-week period in 2007 using administrative records. Service utilisation incidence rates (population information obtained from de-identified cancer registry data) and incidence rate ratios were calculated by gender, age group, cancer type, socioeconomic status and location. Results: The Information services (52%, n = 4,932) were the most popular Cancer Council of Western Australia (CCWA) services followed by Emotional Support services (21%, n =  2,045). All CCWA services were more likely to be accessed by those with a lower socioeconomic status, except for Clinical Services. The rate of utilisation for patients with cancer in the 65+ years age group was found to be under-serviced relative to the 40–64 years age group. Conclusions: Overall, the study has shown that CCWA services are not provided uniformly (horizontal equity) across strata of socio-economic status. Given that the prevalence of cancer generally increases with socio-economic advantage, the findings were notable in regard to one particular outcome. Results for age indicate that there may be some underlying accessibility issues for the aged population. The findings are consistent with current literature highlighting issues of disadvantage in regard to the ability of elderly persons with cancer to access services and support

Health promotion programs related to the Athens 2004 Olympic and Para Olympic games

BACKGROUND: The Olympic Games constitute a first-class opportunity to promote athleticism and health messages. Little is known, however on the impact of Olympic Games on the development of health-promotion programs for the general population. Our objective was to identify and describe the population-based health-promotion programs implemented in relation to the Athens 2004 Olympic and Para Olympic Games. METHODS: A cross-sectional survey of all stakeholders of the Games, including the Athens 2004 Organizing Committee, all ministries of the Greek government, the National School of Public Health, all municipalities hosting Olympic events and all official private sponsors of the Games, was conducted after the conclusion of the Games. RESULTS: A total of 44 agencies were surveyed, 40 responded (91%), and ten (10) health-promotion programs were identified. Two programs were implemented by the Athens 2004 Organizing Committee, 2 from the Greek ministries, 2 from the National School of Public Health, 1 from municipalities, and 3 from official private sponsors of the Games. The total cost of the programs was estimated at 943,000 Euros; a relatively small fraction (0.08%) of the overall cost of the Games. CONCLUSION: Greece has made a small, however, significant step forward, on health promotion, in the context of the Olympic Games. The International Olympic Committee and the future hosting countries, including China, are encouraged to elaborate on this idea and offer the world a promising future for public health

The homocysteine controversy

Mild to moderate hyperhomocysteinemia has been identified as a strong predictor of cardiovascular disease, independent from classical atherothrombotic risk factors. In the last decade, a number of large intervention trials using B vitamins have been performed and have shown no benefit of homocysteine-lowering therapy in high-risk patients. In addition, Mendelian randomization studies failed to convincingly demonstrate that a genetic polymorphism commonly associated with higher homocysteine levels (methylenetetrahydrofolate reductase 677 C>T) is a risk factor for cardiovascular disease. Together, these findings have cast doubt on the role of homocysteine in cardiovascular disease pathogenesis, and the homocysteine hypothesis has turned into a homocysteine controversy. In this review, we attempt to find solutions to this controversy. First, we explain that the Mendelian randomization analyses have limitations that preclude final conclusions. Second, several characteristics of intervention trials limit interpretation and generalizability of their results. Finally, the possibility that homocysteine lowering is in itself beneficial but is offset by adverse side effects of B vitamins on atherosclerosis deserves serious attention. As we explain, such side effects may relate to direct adverse effects of the B-vitamin regimen (in particular, the use of high-dose folic acid) or to proinflammatory and proproliferative effects of B vitamins on advanced atherosclerotic lesions