Comparison of Dixon Sequences for Estimation of Percent Breast Fibroglandular Tissue

Objectives

To evaluate sources of error in the Magnetic Resonance Imaging (MRI) measurement of percent fibroglandular tissue (%FGT) using two-point Dixon sequences for fat-water separation.

Methods

Ten female volunteers (median age: 31 yrs, range: 23–50 yrs) gave informed consent following Research Ethics Committee approval. Each volunteer was scanned twice following repositioning to enable an estimation of measurement repeatability from high-resolution gradient-echo (GRE) proton-density (PD)-weighted Dixon sequences. Differences in measures of %FGT attributable to resolution, T₁ weighting and sequence type were assessed by comparison of this Dixon sequence with low-resolution GRE PD-weighted Dixon data, and against gradient-echo (GRE) or spin-echo (SE) based T₁-weighted Dixon datasets, respectively.

Results

%FGT measurement from high-resolution PD-weighted Dixon sequences had a coefficient of repeatability of ±4.3%. There was no significant difference in %FGT between high-resolution and low-resolution PD-weighted data. Values of %FGT from GRE and SE T₁-weighted data were strongly correlated with that derived from PD-weighted data (r = 0.995 and 0.96, respectively). However, both sequences exhibited higher mean %FGT by 2.9% (p < 0.0001) and 12.6% (p < 0.0001), respectively, in comparison with PD-weighted data; the increase in %FGT from the SE T₁-weighted sequence was significantly larger at lower breast densities.

Conclusion

Although measurement of %FGT at low resolution is feasible, T₁ weighting and sequence type impact on the accuracy of Dixon-based %FGT measurements; Dixon MRI protocols for %FGT measurement should be carefully considered, particularly for longitudinal or multi-centre studies.     

Assessment of the Characteristics of Orientation Distribution Functions in HARDI Using Morphological Metrics

Orientation distribution functions (ODFs) are widely used to resolve fiber crossing problems in high angular resolution diffusion imaging (HARDI). The characteristics of the ODFs are often assessed using a visual criterion, although the use of objective criteria is also reported, which are directly borrowed from classic signal and image processing theory because they are intuitive and simple to compute. However, they are not always pertinent for the characterization of ODFs. We propose a more general paradigm for assessing the characteristics of ODFs. The idea consists in regarding an ODF as a three-dimensional (3D) point cloud, projecting the 3D point cloud onto an angle-distance map, constructing an angle-distance matrix, and calculating metrics such as length ratio, separability, and uncertainty. The results from both simulated and real data show that the proposed metrics allow for the assessment of the characteristics of ODFs in a quantitative and relatively complete manner.     

Differential Infectivities among Different Japanese Encephalitis Virus Genotypes in Culex quinquefasciatus Mosquitoes

During the last 20 years, the epidemiology of Japanese encephalitis virus (JEV) has changed significantly in its endemic regions due to the gradual displacement of the previously dominant genotype III (GIII) with clade b of GI (GI-b). Whilst there is only limited genetic difference distinguishing the two GI clades (GI-a and GI-b), GI-b has shown a significantly wider and more rapid dispersal pattern in several regions in Asia than the GI-a clade, which remains restricted in its geographic distribution since its emergence. Although previously published molecular epidemiological evidence has shown distinct phylodynamic patterns, characterization of the two GI clades has only been limited to in vitro studies. In this study, Culex quinquefasciatus, a known competent JEV mosquito vector species, was orally challenged with three JEV strains each representing GI-a, GI-b, and GIII, respectively. Infection and dissemination were determined based on the detection of infectious viruses in homogenized mosquitoes. Detection of JEV RNA in mosquito saliva at 14 days post infection indicated that Cx. quinquefasciatus can be a competent vector species for both GI and GIII strains. Significantly higher infection rates in mosquitoes exposed to the GI-b and GIII strains than the GI-a strain suggest infectivity in arthropod vectors may lead to the selective advantage of previously and currently dominant genotypes. It could thus play a role in enzootic transmission cycles for the maintenance of JEV if this virus were ever to be introduced into North America.     

L1 Cell Adhesion Molecule-Specific Chimeric Antigen Receptor-Redirected Human T Cells Exhibit Specific and Efficient Antitumor Activity against Human Ovarian Cancer in Mice

New therapeutic modalities are needed for ovarian cancer, the most lethal gynecologic malignancy. Recent clinical trials have demonstrated the impressive therapeutic potential of adoptive therapy using chimeric antigen receptor (CAR)-redirected T cells to target hematological cancers, and emerging studies suggest a similar impact may be achieved for solid cancers. We sought determine whether genetically-modified T cells targeting the CE7-epitope of L1-CAM, a cell adhesion molecule aberrantly expressed in several cancers, have promise as an immunotherapy for ovarian cancer, first demonstrating that L1-CAM was highly over-expressed on a panel of ovarian cancer cell lines, primary ovarian tumor tissue specimens, and ascites-derived primary cancer cells. Human central memory derived T cells (T_CM) were then genetically modified to express an anti-L1-CAM CAR (CE7R), which directed effector function upon tumor antigen stimulation as assessed by in vitro cytokine secretion and cytotoxicity assays. We also found that CE7R⁺ T cells were able to target primary ovarian cancer cells. Intraperitoneal (i.p.) administration of CE7R⁺ T_CM induced a significant regression of i.p. established SK-OV-3 xenograft tumors in mice, inhibited ascites formation, and conferred a significant survival advantage compared with control-treated animals. Taken together, these studies indicate that adoptive transfer of L1-CAM-specific CE7R⁺ T cells may offer a novel and effective immunotherapy strategy for advanced ovarian cancer.     

Plasma tPA-Activity and Progression of Cerebral White Matter Hyperintensities in Lacunar Stroke Patients

Introduction

Tissue plasminogen activator (tPA)-activity and plasminogen activator inhibitor type 1 (PAI-1) antigen are considered to be haemostasis-related markers of endothelial activation and relate to presence of cerebral white matter hyperintensities (WMH) as was earlier shown in a cross-sectional study. We investigated whether tPA-activity and PAI-1 levels are associated with WMH progression in a longitudinal study.

Methods

In 127 first-ever lacunar stroke patients in whom baseline brain MRI and plasma levels of tPA-activity and PAI-1-antigen were available, we obtained a 2-year follow-up MRI. We assessed WMH progression by a visual WMH change scale. We determined the relationship between levels of tPA-activity and PAI-1 and WMH progression, by logistic regression analysis.

Results

Plasma tPA-activity was associated with periventricular WMH progression (OR 2.36, 95% CI 1.01–5.49, with correction for age and sex and baseline presence of WMH), but not with deep or any (periventricular and/or deep) WMH progression. PAI-1 levels were lower in patients with WMH progression, but these results were not significant.

Conclusion

We found a relationship between plasma tPA-activity and progression of periventricular WMH. More research is needed to determine whether there is a (direct) role of tPA in the development and progression of WMH.     

Objectively Measured Physical Activity in European Adults: Cross-Sectional Findings from the Food4Me Study

Background

Comparisons of objectively measured physical activity (PA) between residents of European countries measured concurrently with the same protocol are lacking. We aimed to compare PA between the seven European countries involved in the Food4Me Study, using accelerometer data collected remotely via the Internet.

Methods

Of the 1607 participants recruited, 1287 (539 men and 748 women) provided at least 3 weekdays and 2 weekend days of valid accelerometer data (TracmorD) at baseline and were included in the present analyses.

Results

Men were significantly more active than women (physical activity level = 1.74 vs. 1.70, p < 0.001). Time spent in light PA and moderate PA differed significantly between countries but only for women. Adherence to the World Health Organization recommendation to accumulate at least 150 min of moderate-equivalent PA weekly was similar between countries for men (range: 54–65%) but differed significantly between countries for women (range: 26–49%). Prevalence estimates decreased substantially for men and women in all seven countries when PA guidelines were defined as achieving 30 min of moderate and vigorous PA per day.

Conclusions

We were able to obtain valid accelerometer data in real time via the Internet from 80% of participants. Although our estimates are higher compared with data from Sweden, Norway, Portugal and the US, there is room for improvement in PA for all countries involved in the Food4Me Study.     

Examination of Duct Physiology in the Human Mammary Gland

BackgroundThe human breast comprise several ductal systems, or lobes, which contain a small amount of fluid containing cells, hormones, proteins and metabolites. The complex physiology of these ducts is likely a contributing factor to the development of breast cancer, especially given that the vast majority of breast cancers begin in a single lobular unit.MethodsWe examined the levels of total protein, progesterone, estradiol, estrone sulfate, dehydroepiandrosterone sulfate, and macrophages in ductal fluid samples obtained from 3 ducts each in 78 women, sampled twice over a 6 month period. Samples were processed for both cytological and molecular analysis. Intraclass correlation coefficients and mixed models were utilized to identify significant data.ResultsWe found that the levels of these ductal fluid components were generally uncorrelated among ducts within a single breast and over time, suggesting that each lobe within the breast has a distinct physiology. However, we also found that estradiol was more correlated in women who were nulliparous or produced nipple aspirate fluid.ConclusionsOur results provide evidence that the microenvironment of any given lobular unit is unique to that individual unit, findings that may provide clues about the initiation and development of ductal carcinomas.     

Long-Term Secondary Care Costs of Endometrial Cancer: A Prospective Cohort Study Nested within the United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS)

BackgroundThere is limited evidence on the costs of Endometrial Cancer (EC) by stage of disease. We estimated the long-term secondary care costs of EC according to stage at diagnosis in an English population-based cohort.MethodsWomen participating in UKCTOCS and diagnosed with EC following enrolment (2001–2005) and prior to 31^st Dec 2009 were identified to have EC through multiple sources. Survival was calculated through data linkage to death registry. Costs estimates were derived from hospital records accessed from Hospital Episode Statistics (HES) with additional patient level covariates derived from case notes and patient questionnaires. Missing and censored data was imputed using Multiple Imputation. Regression analysis of cost and survival was undertaken.Results491 of 641 women with EC were included. Five year total costs were strongly dependent on stage, ranging from £9,475 (diagnosis at stage IA/IB) to £26,080 (diagnosis at stage III). Stage, grade and BMI were the strongest predictors of costs. The majority of costs for stage I/II EC were incurred in the first six months after diagnosis while for stage III / IV considerable costs accrued after the first six months.ConclusionsIn addition to survival advantages, there are significant cost savings if patients with EC are detected earlier.     

New Insights on Wood Dimensional Stability Influenced by Secondary Metabolites: The Case of a Fast-Growing Tropical Species Bagassa guianensis Aubl.

Challenging evaluation of tropical forest biodiversity requires the reporting of taxonomic diversity but also the systematic characterization of wood properties in order to discover new promising species for timber industry. Among wood properties, the dimensional stability is regarded as a major technological characteristic to validate whether a wood species is adapted to commercial uses. Cell structure and organization are known to influence the drying shrinkage making wood density and microfibrils angle markers of choice to predict wood dimensional stability. On the contrary the role of wood extractive content remains unclear. This work focuses on the fast-growing tropical species Bagassa guianensis and we report herein a correlation between heartwood drying shrinkage and extractive content. Chemical extractions and shrinkage experiments were performed on separate wood twin samples to better evaluate correctly how secondary metabolites influence the wood shrinkage behaviour. Extractive content were qualitatively and quantitatively analysed using HPLC and NMR spectroscopy. We found that B guianensis heartwood has a homogeneous low shrinkage along its radius that could not be explained only by its basic density. In fact the low drying shrinkage is correlated to the high extractive content and a corrected model to improve the prediction of wood dimensional stability is presented. Additionally NMR experiments conducted on sapwood and heartwood extracts demonstrate that secondary metabolites biosynthesis occurs in sapwood thus revealing B. guianensis as a Juglans-Type heartwood formation. This work demonstrates that B. guianensis, a fast-growing species associated with high durability and high dimensional stability, is a good candidate for lumber production and commercial purposes.     

Reasons for Missing Antiretroviral Therapy: Results from a Multi-Country Study in Tanzania,Uganda, and Zambia

Objectives

To identify the reasons patients miss taking their antiretroviral therapy (ART) and the proportion who miss their ART because of symptoms; and to explore the association between symptoms and incomplete adherence.

Methods

Secondary analysis of data collected during a cross-sectional study that examined ART adherence among adults from 18 purposefully selected sites in Tanzania, Uganda, and Zambia. We interviewed 250 systematically selected patients per facility (≥18 years) on reasons for missing ART and symptoms they had experienced (using the HIV Symptom Index). We abstracted clinical data from the patients’ medical, pharmacy, and laboratory records. Incomplete adherence was defined as having missed ART for at least 48 consecutive hours during the past 3 months.

Results

Twenty-nine percent of participants reported at least one reason for having ever missed ART (1278/4425). The most frequent reason was simply forgetting (681/1278 or 53%), followed by ART-related hunger or not having enough food (30%), and symptoms (12%). The median number of symptoms reported by participants was 4 (IQR: 2–7). Every additional symptom increased the odds of incomplete adherence by 12% (OR: 1.1, 95% CI: 1.1–1.2). Female participants and participants initiated on a regimen containing stavudine were more likely to report greater numbers of symptoms.

Conclusions

Symptoms were a common reason for missing ART, together with simply forgetting and food insecurity. A combination of ART regimens with fewer side effects, use of mobile phone text message reminders, and integration of food supplementation and livelihood programmes into HIV programmes, have the potential to decrease missed ART and hence to improve adherence and the outcomes of ART programmes.