Metastases in normal-sized pelvic lymph nodes: detection with diffusion-weighted MR imaging

PURPOSE To prospectively assess the diagnostic performance of diffusion-weighted (DW) magnetic resonance (MR) imaging in the detection of pelvic lymph node metastases in patients with prostate and/or bladder cancer staged as N0 with preoperative cross-sectional imaging. MATERIALS AND METHODS This study was approved by an independent ethics committee. Written informed consent was obtained from all patients. Patients with no enlarged lymph nodes on preoperative cross-sectional images who were scheduled for radical resection of the primary tumor and extended pelvic lymph node dissection were enrolled. All patients were examined with a 3-T MR unit, and examinations included conventional and DW MR imaging of the entire pelvis. Image analysis was performed by three independent readers blinded to any clinical information. Metastases were diagnosed on the basis of high signal intensity on high b value DW MR images and morphologic features (shape, border). Histopathologic examination served as the standard of reference. Sensitivity and specificity were calculated, and bias-corrected 95% confidence intervals (CIs) were obtained with the bootstrap method. The Fleiss and Cohen κ and median test were applied for statistical analyses. RESULTS A total of 4846 lymph nodes were resected in 120 patients. Eighty-eight lymph node metastases were found in 33 of 120 patients (27.5%). Short-axis diameter of these metastases was less than or equal to 3 mm in 68, more than 3 mm to 5 mm in 13, more than 5 mm to 8 mm in five; and more than 8 mm in two. On a per-patient level, the three readers correctly detected metastases in 26 (79%; 95% CI: 64%, 91%), 21 (64%; 95% CI: 45%, 79%), and 25 (76%; 95% CI: 60%, 90%) of the 33 patients with metastases, with respective specificities of 85% (95% CI: 78%, 92%), 79% (95% CI: 70%, 88%), and 84% (95% CI: 76%, 92%). Analyzed according to hemipelvis, lymph node metastases were detected with histopathologic examination in 44 of 240 pelvic sides (18%); the three readers correctly detected these on DW MR images in 26 (59%; 95% CI: 45%, 73%), 19 (43%; 95% CI: 27%, 57%), and 28 (64%; 95% CI: 47%, 78%) of the 44 cases. CONCLUSION DW MR imaging enables noninvasive detection of small lymph node metastases in normal-sized nodes in a substantial percentage of patients with prostate and bladder cancer diagnosed as N0 with conventional cross-sectional imaging techniques.

Diffusion-weighted magnetic resonance imaging detects significant prostate cancer with high probability

PURPOSE We prospectively assessed the diagnostic accuracy of diffusion-weighted magnetic resonance imaging for detecting significant prostate cancer. MATERIALS AND METHODS We performed a prospective study of 111 consecutive men with prostate and/or bladder cancer who underwent 3 Tesla diffusion-weighted magnetic resonance imaging of the pelvis without an endorectal coil before radical prostatectomy (78) or cystoprostatectomy (33). Three independent readers blinded to clinical and pathological data assigned a prostate cancer suspicion grade based on qualitative imaging analysis. Final pathology results of prostates with and without cancer served as the reference standard. Primary outcomes were the sensitivity and specificity of diffusion-weighted magnetic resonance imaging for detecting significant prostate cancer with significance defined as a largest diameter of the index lesion of 1 cm or greater, extraprostatic extension, or Gleason score 7 or greater on final pathology assessment. Secondary outcomes were interreader agreement assessed by the Fleiss κ coefficient and image reading time. RESULTS Of the 111 patients 93 had prostate cancer, which was significant in 80 and insignificant in 13, and 18 had no prostate cancer on final pathology results. The sensitivity and specificity of diffusion-weighted magnetic resonance imaging for detecting significant PCa was 89% to 91% and 77% to 81%, respectively, for the 3 readers. Interreader agreement was good (Fleiss κ 0.65 to 0.74). Median reading time was between 13 and 18 minutes. CONCLUSIONS Diffusion-weighted magnetic resonance imaging (3 Tesla) is a noninvasive technique that allows for the detection of significant prostate cancer with high probability without contrast medium or an endorectal coil, and with good interreader agreement and a short reading time. This technique should be further evaluated as a tool to stratify patients with prostate cancer for individualized treatment options.

Repeated electrical stimulations as a tool to evoke temporal summation of nociceptive inputs in healthy, non-medicated experimental sheep.

The nociceptive withdrawal reflex (NWR) model is used in animal pain research to quantify nociception. The aim of this study was to evaluate the NWR evoked by repeated stimulations in healthy, non-medicated standing sheep. Repeated electrical stimulations were applied at 5Hz for 2s to the digital nerves of the right thoracic and the pelvic limbs of 25 standing sheep. The stimulation intensities applied were fractions (0.5, 0.6, 0.7, 0.8, 0.9 and 1) of the individual previously determined nociceptive threshold (It) after single stimulation. Surface-electromyographic activity (EMG) was recorded from the deltoid, the femoral biceps or the peroneus tertius muscles. The repeated stimulation threshold (RS It) was reached if at least one stimulus in the train was followed by a reflex with a minimal root-mean-square-amplitude (RMSA) of 20μV. The behavioural reaction following each series of stimulations was scored on a scale from 0 (no reaction) to 5 (vigorous whole-body reaction). For the deltoid muscle, RS It was 2.3mA (1.6-3mA) with a reaction score of 2 (1-2) and at a fraction of 0.6 (0.5-0.8)×It. For the biceps femoris muscle, RS It was 2.9mA (2.6-4mA) with a reaction score of 1 (1-2) at a fraction of and 0.55 (0.4-0.7)×It while for the peroneus tertius muscle RS It was 3mA (2.8-3.5mA) with a reaction score of 1 (1-2) and at a fraction of 0.8 (0.8-0.95)×It. Both, RMSA and reaction scores increased significantly with increasing stimulation intensities in all muscles (p<0.001). The repeated application of electrical stimuli led to temporal summation of nociceptive inputs and therefore a reduction of the stimulus intensity evoking a withdrawal reaction in healthy, standing sheep. Data achieved in this study can now serve as reference for further clinical or experimental applications of the model in this species.

The structural substrate of brain function: analysis of brain structural networks based on diffusion-weighted imaging

The brain is a complex neural network with a hierarchical organization and the mapping of its elements and connections is an important step towards the understanding of its function. Recent developments in diffusion-weighted imaging have provided the opportunity to reconstruct the whole-brain structural network in-vivo at a large scale level and to study the brain structural substrate in a framework that is close to the current understanding of brain function. However, methods to construct the connectome are still under development and they should be carefully evaluated. To this end, the first two studies included in my thesis aimed at improving the analytical tools specific to the methodology of brain structural networks. The first of these papers assessed the repeatability of the most common global and local network metrics used in literature to characterize the connectome, while in the second paper the validity of further metrics based on the concept of communicability was evaluated. Communicability is a broader measure of connectivity which accounts also for parallel and indirect connections. These additional paths may be important for reorganizational mechanisms in the presence of lesions as well as to enhance integration in the network. These studies showed good to excellent repeatability of global network metrics when the same methodological pipeline was applied, but more variability was detected when considering local network metrics or when using different thresholding strategies. In addition, communicability metrics have been found to add some insight into the integration properties of the network by detecting subsets of nodes that were highly interconnected or vulnerable to lesions. The other two studies used methods based on diffusion-weighted imaging to obtain knowledge concerning the relationship between functional and structural connectivity and about the etiology of schizophrenia. The third study integrated functional oscillations measured using electroencephalography (EEG) and functional magnetic resonance imaging (fMRI) as well as diffusion-weighted imaging data. The multimodal approach that was applied revealed a positive relationship between individual fluctuations of the EEG alpha-frequency and diffusion properties of specific connections of two resting-state networks. Finally, in the fourth study diffusion-weighted imaging was used to probe for a relationship between the underlying white matter tissue structure and season of birth in schizophrenia patients. The results are in line with the neurodevelopmental hypothesis of early pathological mechanisms as the origin of schizophrenia. The different analytical approaches selected in these studies also provide arguments for discussion of the current limitations in the analysis of brain structural networks. To sum up, the first studies presented in this thesis illustrated the potential of brain structural network analysis to provide useful information on features of brain functional segregation and integration using reliable network metrics. In the other two studies alternative approaches were presented. The common discussion of the four studies enabled us to highlight the benefits and possibilities for the analysis of the connectome as well as some current limitations.

Delayed HIV diagnosis and initiation of antiretroviral therapy: inequalities by educational level, COHERE in EuroCoord.

OBJECTIVES In Europe and elsewhere, health inequalities among HIV-positive individuals are of concern. We investigated late HIV diagnosis and late initiation of combination antiretroviral therapy (cART) by educational level, a proxy of socioeconomic position. DESIGN AND METHODS We used data from nine HIV cohorts within COHERE in Austria, France, Greece, Italy, Spain and Switzerland, collecting data on level of education in categories of the UNESCO/International Standard Classification of Education standard classification: non-completed basic, basic, secondary and tertiary education. We included individuals diagnosed with HIV between 1996 and 2011, aged at least 16 years, with known educational level and at least one CD4 cell count within 6 months of HIV diagnosis. We examined trends by education level in presentation with advanced HIV disease (AHD) (CD4 <200 cells/μl or AIDS within 6 months) using logistic regression, and distribution of CD4 cell count at cART initiation overall and among presenters without AHD using median regression. RESULTS Among 15 414 individuals, 52, 45,37, and 31% with uncompleted basic, basic, secondary and tertiary education, respectively, presented with AHD (P trend <0.001). Compared to patients with tertiary education, adjusted odds ratios of AHD were 1.72 (95% confidence interval 1.48-2.00) for uncompleted basic, 1.39 (1.24-1.56) for basic and 1.20 (1.08-1.34) for secondary education (P < 0.001). In unadjusted and adjusted analyses, median CD4 cell count at cART initiation was lower with poorer educational level. CONCLUSIONS Socioeconomic inequalities in delayed HIV diagnosis and initiation of cART are present in European countries with universal healthcare systems and individuals with lower educational level do not equally benefit from timely cART initiation.

Diffusion-weighted MR imaging of upper abdominal organs: field strength and intervendor variability of apparent diffusion coefficients

PURPOSE To determine the variability of apparent diffusion coefficient (ADC) values in various anatomic regions in the upper abdomen measured with magnetic resonance (MR) systems from different vendors and with different field strengths. MATERIALS AND METHODS Ten healthy men (mean age, 36.6 years ± 7.7 [standard deviation]) gave written informed consent to participate in this prospective ethics committee-approved study. Diffusion-weighted (DW) MR imaging was performed in each subject with 1.5- and 3.0-T MR systems from each of three vendors at two institutions. Two readers independently measured ADC values in seven upper abdominal regions (left and right liver lobe, gallbladder, pancreas, spleen, and renal cortex and medulla). ADC values were tested for interobserver differences, as well as for differences related to field strength and vendor, with repeated-measures analysis of variance; coefficients of variation (CVs) and variance components were calculated. RESULTS Interreader agreement was excellent (intraclass coefficient, 0.876). ADC values were (77.5-88.8) ×10(-5) mm(2)/sec in the spleen and (250.6-278.5) ×10(-5) mm(2)/sec in the gallbladder. There were no significant differences between ADC values measured at 1.5 T and those measured at 3.0 T in any anatomic region (P >.10 for all). In two of seven regions at 1.5 T (left and right liver lobes, P < .023) and in four of seven regions at 3.0 T (left liver lobe, pancreas, and renal cortex and medulla, P < .008), intervendor differences were significant. CVs ranged from 7.0% to 27.1% depending on the anatomic location. CONCLUSION Despite significant intervendor differences in ADC values of various anatomic regions of the upper abdomen, ADC values of the gallbladder, pancreas, spleen, and kidney may be comparable between MR systems from different vendors and between different field strengths.

Whole-Brain Susceptibility-Weighted Thrombus Imaging in Stroke: Fragmented Thrombi Predict Worse Outcome.

BACKGROUND AND PURPOSE The prevalence and clinical importance of primarily fragmented thrombi in patients with acute ischemic stroke remains elusive. Whole-brain SWI was used to detect multiple thrombus fragments, and their clinical significance was analyzed. MATERIALS AND METHODS Pretreatment SWI was analyzed for the presence of a single intracranial thrombus or multiple intracranial thrombi. Associations with baseline clinical characteristics, complications, and clinical outcome were studied. RESULTS Single intracranial thrombi were detected in 300 (92.6%), and multiple thrombi, in 24 of 324 patients (7.4%). In 23 patients with multiple thrombi, all thrombus fragments were located in the vascular territory distal to the primary occluding thrombus; in 1 patient, thrombi were found both in the anterior and posterior circulation. Only a minority of thrombus fragments were detected on TOF-MRA, first-pass gadolinium-enhanced MRA, or DSA. Patients with multiple intracranial thrombi presented with more severe symptoms (median NIHSS scores, 15 versus 11; P = .014) and larger ischemic areas (median DWI ASPECTS, 5 versus 7; P = .006); good collaterals, rated on DSA, were fewer than those in patients with a single thrombus (21.1% versus 44.2%, P = .051). The presence of multiple thrombi was a predictor of unfavorable outcome at 3 months (P = .040; OR, 0.251; 95% CI, 0.067-0.939). CONCLUSIONS Patients with multiple intracranial thrombus fragments constitute a small subgroup of patients with stroke with a worse outcome than patients with single thrombi.

Shaping gender inequalities: critical moments and critical places

Purpose – There is much scientific interest in the connection between the emergence of gender-based inequalities and key biographical transition points of couples in long-term relationships. Little empirical research is available comparing the evolution of a couple’s respective professional careers over space and time. The purpose of this paper is to contribute to filling this gap by addressing the following questions: what are the critical biographical moments when gender (in)equalities within a relationship begin to arise and consolidate? Which biographical decisions precede and follow such critical moments? How does decision making at critical moments impact the opportunities of both relationship partners in gaining equal access to paid employment? Design/methodology/approach – These questions are addressed from the perspectives of intersectionality and economic citizenship. Biographical interviewing is used to collect the personal and professional narratives of Swiss-, bi-national and migrant couples. The case study of a Swiss-Norwegian couple illustrates typical processes by which many skilled migrant women end up absently or precariously employed. Findings – Analysis reveals that the Scandinavian woman’s migration to Switzerland is a primary and critical moment for emerging inequality, which is then reinforced by relocation (to a small town characterized by conservative gender values) and the subsequent births of their children. It is concluded that factors of traditional gender roles, ethnicity and age intersect to create a hierarchical situation which affords the male Swiss partner more weight in terms of decision making and career advancement. Practical implications – The paper’s findings are highly relevant to the formulation of policies regarding gender inequalities and the implementation of preventive programmes within this context. Originality/value – Little empirical research is available comparing the evolution of a couple’s respective professional careers over space and time. The originality of this paper is to fill this research gap; to include migration as a critical moment for gender inequalities; to use an intersectional and geographical perspective that have been given scant attention in the literature; to use the original concept of economic citizenship; and to examine the case of a bi-national couple, which has so far not been examined by the literature on couple relationships.

Separation of small metabolites and lipids in spectra from biopsies by diffusion-weighted HR-MAS NMR: a feasibility study.

High Resolution Magic Angle Spinning (HR-MAS) NMR allows metabolic characterization of biopsies. HR-MAS spectra from tissues of most organs show strong lipid contributions that are overlapping metabolite regions, which hamper metabolite estimation. Metabolite quantification and analysis would benefit from a separation of lipids and small metabolites. Generally, a relaxation filter is used to reduce lipid contributions. However, the strong relaxation filter required to eliminate most of the lipids also reduces the signals for small metabolites. The aim of our study was therefore to investigate different diffusion editing techniques in order to employ diffusion differences for separating lipid and small metabolite contributions in the spectra from different organs for unbiased metabonomic analysis. Thus, 1D and 2D diffusion measurements were performed, and pure lipid spectra that were obtained at strong diffusion weighting (DW) were subtracted from those obtained at low DW, which include both small metabolites and lipids. This subtraction yielded almost lipid free small metabolite spectra from muscle tissue. Further improved separation was obtained by combining a 1D diffusion sequence with a T2-filter, with the subtraction method eliminating residual lipids from the spectra. Similar results obtained for biopsies of different organs suggest that this method is applicable in various tissue types. The elimination of lipids from HR-MAS spectra and the resulting less biased assessment of small metabolites have potential to remove ambiguities in the interpretation of metabonomic results. This is demonstrated in a reproducibility study on biopsies from human muscle.

Cultural capital and smoking in young adults: applying new indicators to explore social inequalities in health behaviour.

BACKGROUND Associations between social status and health behaviours are well documented, but the mechanisms involved are less understood. Cultural capital theory may contribute to a better understanding by expanding the scope of inequality indicators to include individuals' knowledge, skills, beliefs and material goods to examine how these indicators impact individuals' health lifestyles. We explore the structure and applicability of a set of cultural capital indicators in the empirical exploration of smoking behaviour among young male adults. METHODS We analysed data from the Swiss Federal Survey of Adolescents (CH-X) 2010-11 panel of young Swiss males (n = 10 736). A set of nine theoretically relevant variables (including incorporated, institutionalized and objectified cultural capital) were investigated using exploratory factor analysis. Regression models were run to observe the association between factor scores and smoking outcomes. Outcome measures consisted of daily smoking status and the number of cigarettes smoked by daily smokers. RESULTS Cultural capital indicators aggregated in a three-factor solution representing 'health values', 'education and knowledge' and 'family resources'. Each factor score predicted the smoking outcomes. In young males, scoring low on health values, education and knowledge and family resources was associated with a higher risk of being a daily smoker and of smoking more cigarettes daily. CONCLUSION Cultural capital measures that include, but go beyond, educational attainment can improve prediction models of smoking in young male adults. New measures of cultural capital may thus contribute to our understanding of the social status-based resources that individuals can use towards health behaviours.

Range-based Weighted-likelihood Particle Filter for RSS-based Indoor Tracking

Attractive business cases in various application fields contribute to the sustained long-term interest in indoor localization and tracking by the research community. Location tracking is generally treated as a dynamic state estimation problem, consisting of two steps: (i) location estimation through measurement, and (ii) location prediction. For the estimation step, one of the most efficient and low-cost solutions is Received Signal Strength (RSS)-based ranging. However, various challenges - unrealistic propagation model, non-line of sight (NLOS), and multipath propagation - are yet to be addressed. Particle filters are a popular choice for dealing with the inherent non-linearities in both location measurements and motion dynamics. While such filters have been successfully applied to accurate, time-based ranging measurements, dealing with the more error-prone RSS based ranging is still challenging. In this work, we address the above issues with a novel, weighted likelihood, bootstrap particle filter for tracking via RSS-based ranging. Our filter weights the individual likelihoods from different anchor nodes exponentially, according to the ranging estimation. We also employ an improved propagation model for more accurate RSS-based ranging, which we suggested in recent work. We implemented and tested our algorithm in a passive localization system with IEEE 802.15.4 signals, showing that our proposed solution largely outperforms a traditional bootstrap particle filter.

Cohort Profile: The Interdisciplinary Study of Inequalities in Smoking (ISIS)

The Interdisciplinary Study of Inequalities in Smoking (ISIS) is a cohort study investigating the joint effects of residents' socio-demographic characteristics and neighbourhood attributes on the social distribution of smoking in a young adult population. Smoking is a behaviour with an increasingly steep social class gradient; smoking prevalence among young adults is no longer declining at the same rate as among the rest of the population, and there is evidence of growing place-based disparities in smoking. ISIS was established to examine these pressing concerns. The ISIS sample comprises non-institutionalized individuals aged 18-25 years, who are proficient in English and/or French and who had been living at their current address in Montréal, Canada, for at least 1 year at time of first contact. Two waves of data have been collected: baseline data were collected November 2011-September 2012 (n = 2093), and a second wave of data was collected January-June 2014 (n = 1457). Data were collected from respondents using a self-administered questionnaire, developed by the research team based on sociological theory, which includes questions concerning social, economic, cultural and biological capital, and activity space as well as smoking behaviour. Data are available upon request from [katherine.frohlich@umontreal.ca].

Gender inequalities in the response to combination antiretroviral therapy over time: the Swiss HIV Cohort Study

OBJECTIVES Gender-specific data on the outcome of combination antiretroviral therapy (cART) are a subject of controversy. We aimed to compare treatment responses between genders in a setting of equal access to cART over a 14-year period. METHODS Analyses included treatment-naïve participants in the Swiss HIV Cohort Study starting cART between 1998 and 2011 and were restricted to patients infected by heterosexual contacts or injecting drug use, excluding men who have sex with men. RESULTS A total of 3925 patients (1984 men and 1941 women) were included in the analysis. Women were younger and had higher CD4 cell counts and lower HIV RNA at baseline than men. Women were less likely to achieve virological suppression < 50 HIV-1 RNA copies/mL at 1 year (75.2% versus 78.1% of men; P = 0.029) and at 2 years (77.5% versus 81.1%, respectively; P = 0.008), whereas no difference between sexes was observed at 5 years (81.3% versus 80.5%, respectively; P = 0.635). The probability of virological suppression increased in both genders over time (test for trend, P < 0.001). The median increase in CD4 cell count at 1, 2 and 5 years was generally higher in women during the whole study period, but it gradually improved over time in both sexes (P < 0.001). Women also were more likely to switch or stop treatment during the first year of cART, and stops were only partly driven by pregnancy. In multivariate analysis, after adjustment for sociodemographic factors, HIV-related factors, cART and calendar period, female gender was no longer associated with lower odds of virological suppression. CONCLUSIONS Gender inequalities in the response to cART are mainly explained by the different prevalence of socioeconomic characteristics in women compared with men.