Assessment of melanocytic skin lesions with a high-definition laser Doppler imaging system.

BACKGROUND: Early detection is a major goal in the management of malignant melanoma. Besides clinical assessment many noninvasive technologies such as dermoscopy, digital dermoscopy and in vivo laser scanner microscopy are used as additional methods. Herein we tested a system to assess lesional perfusion as a tool for early melanoma detection.¦METHODS: Laser Doppler flow (FluxExplorer) and mole analyser (MA) score (FotoFinder) were applied to histologically verified melanocytic nevi (33) and malignant melanomas (12).¦RESULTS: Mean perfusion and MA scores were significantly increased in melanoma compared to nevi. However, applying an empirically determined threshold of 16% perfusion increase only 42% of the melanomas fulfilled the criterion of malignancy, whereas with the mole analyzer score 82% of the melanomas fulfilled the criterion of malignancy.¦CONCLUSION: Laser Doppler imaging is a highly sensitive technology to assess skin and skin tumor perfusion in vivo. Although mean perfusion is higher in melanomas compared to nevi the high numbers of false negative results hamper the use of this technology for early melanoma detection.

Comparative Study of a Real-Time PCR Assay Targeting senX3-regX3 versus Other Molecular Strategies Commonly Used in the Diagnosis of Tuberculosis.

BACKGROUND Nucleic acid amplification tests are increasingly used for the rapid diagnosis of tuberculosis. We undertook a comparative study of the efficiency and diagnostic yield of a real-time PCR senX3-regX3 based assay versus the classical IS6110 target and the new commercial methods. METHODS This single-blind prospective comparative study included 145 consecutive samples: 76 from patients with culture-confirmed tuberculosis (86.8% pulmonary and 13.2% extrapulmonary tuberculosis: 48.7% smear-positive and 51.3% smear-negative) and 69 control samples (24 from patients diagnosed with non-tuberculous mycobacteria infections and 45 from patients with suspected tuberculosis which was eventually ruled out). All samples were tested by two CE-marked assays (Xpert®MTB/RIF and AnyplexTM plus MTB/NTM) and two in-house assays targeting senX3-regX3 and the IS6110 gene. RESULTS The detection limit ranged from 1.00E+01 fg for Anyplex, senX3-regX3 and IS6110 to 1.00E+04 fg for Xpert. All three Xpert, senX3-regX3 and IS6110 assays detected all 37 smear-positive cases. Conversely, Anyplex was positive in 34 (91.9%) smear-positive cases. In patients with smear-negative tuberculosis, differences were observed between the assays; Xpert detected 22 (56.41%) of the 39 smear-negative samples, Anyplex 24 (61.53%), senX3-regX3 28 (71.79%) and IS6110 35 (89.74%). Xpert and senX3-regX3 were negative in all control samples; however, the false positive rate was 8.7% and 13% for Anyplex and IS6110, respectively. The overall sensitivity was 77.6%, 85.7%, 77.3% and 94.7% and the specificity was 100%, 100%, 90.8% and 87.0% for the Xpert, senX3-regX3, Anyplex and IS6110 assays, respectively. CONCLUSION Real-time PCR assays targeting IS6110 lack the desired specificity. The Xpert MTB/RIF and in-house senX3-regX3 assays are both sensitive and specific for the detection of MTBC in both pulmonary and extrapulmonary samples. Therefore, the real time PCR senX3-regX3 based assay could be a useful and complementary tool in the diagnosis of tuberculosis.

Dépistage du cancer pulmonaire par scanner thoracique [Computed tomography screening for lung cancer].

Lung cancer screening has been the focus of intense interest since the publication in 2011 of the NLST trial (National Lung Screening Trial) showing a mortality reduction in smokers undergoing 3-year screening by chest computed tomography. Although these data appear promising, many issues remain to be resolved, such as high rate of false positive cases, risk of overdiagnosis, optimal intervals between screens, duration of the screening process, feasibility, and cost. Structured screening programs appear crucial to guarantee patient information, technical quality, and multidisciplinary management. Despite these uncertainties, several guidelines already state that screening should be performed in patients at risk, whereas investigators stress that more data are needed. How should the primary care physician deal with individual patients requests? This review provides some clues on this complex issue.

Global and local connectivity changes in schizophrenia investigated by diffusion connectome

Background: New ways of representing diffusion data emerged recently and achieved to create structural connectivitymaps in healthy brains (Hagmann P et al. (2008)). These maps have the capacity to study alterations over the entire brain at the connection and network level. This is of high interest in complex disconnection diseases like schizophrenia. In this Pathology where multiple lines of evidence suggest the association of the pathology with abnormalities in neural circuitry and impaired structural connectivity, the diffusion imaging has been widely applied. Despite the large findings, most of the research using the diffusion just uses some scalar map derived from diffusion to show that some markers of white matter integrity are diminished in several areas of the brain (Kyriakopoulos M et al (2008)). Thanks to the structural connectionmatrix constructed by the whole brain tractography, we report in this work the network connectivity alterations in the schizophrenic patients. Methods: We investigated 13 schizophrenic patients as assessed by the DIGS (Diagnostic Interview for genetic studies, DSM IV criteria) and 13 healthy controls. We have got from each volunteer a DT-MRI as well as Qball imaging dataset and a high resolution anatomic T1 performed during the same session; with a 3 T clinical MRI scanner. The controls were matched on age, gender, handedness, and parental social economic-status. For all the subjects, a low resolution connection matrix is obtained by dividing the cortex into 66 gyral based ROIs. A higher resolution matrix is constructed using 250 ROIs as described in Hagmann P et al. (2008). These ROIs are respectively used jointly with the diffusion tractography to construct the high and low resolution densities connection matrices for each subject. In a first step the matrices of the groups are compared in term of connectivity, and not in term of density to check if the pathological group shows a loss of global connectivity. In this context the density connection matrices were binarized. As some local connectivity changes were also suspected, especially in frontal and temporal areas, we have also looked for the areas where the connectivity showed significant changes. Results: The statistical analysis revealed a significant loss of global connectivity in the schizophrenic's brains at level 5%. Furthermore, by constructing specific statistics which represent local connectivity within the anatomical regions (66 ROIs) using the data obtained by the finest resolution (250 ROIs) to improve the robustness, we found the regions that cause this significant loss of connectivity. The significance is observed after multiple testing corrections by the False Discovery Rate. Discussion: The detected regions are almost the same as those reported in the literature as the involved regions in schizophrenia. Most of the connectivity decreases are noted in both hemispheres in the fronto-frontal and temporo-temporal regions as well as some temporal ROIs with their adjacent ROIs in parietal and occipital lobes.

Value of PET/CT versus contrast-enhanced CT in identifying chest wall invasion (T3) by NSCLC [B-671]

Purpose: To determine the diagnostic value of 18F-FDG PET/CT versus contrastenhanced CT in identifying chest wall invasion by NSCLC. Methods and Materials: The primary selection criterion was a peripheral tumor of any size with contact to the chest wall. A total of 25 patients with pathologically proven NSCLC satisfied these criteria. Chest wall invasion was interpreted upon PET/CT when a frank costal or intercostal 18F-FDG uptake was identified with or without concomitant morphologic alterations. On the other hand, the existence of periosteal rib reaction/erosion, chest wall thickening or obliteration of the pleural fat layer either separately or combined were considered essential diagnostic criteria for disease extension into the chest wall upon contrast-enhanced CT. The results were correlated with the final histological analysis. Results: Among the studied cohort, 13/25 (52%) patients had chest wall invasion consistent with T3 disease. Both PET/CT and contrast-enhanced CT successfully identified 12/13 (92%) of these patients. The single false-negative result was due to parietal pleural invasion. On the other hand, one false-positive result was encountered by PET/CT in a dyspneic patient; whereas, CT analysis revealed false-positive results in six patients. In these patients, periosteal rib reaction (n = 2) or asymmetric enlargement of adjacent chest wall muscles (n = 1) were identified along with an obliterated pleural fat layer (n = 6). The sensitivity, specificity, and accuracy of PET/CT and contrast-enhanced CT were 92, 91 and 92% versus 92, 50 and 72%. Conclusion: 18F-FDG PET/CT is an accurate diagnostic modality in identifying.

An Interval Intelligent-based Approach for Fault Detection and Modelling

Not considered in the analytical model of the plant, uncertainties always dramatically decrease the performance of the fault detection task in the practice. To cope better with this prevalent problem, in this paper we develop a methodology using Modal Interval Analysis which takes into account those uncertainties in the plant model. A fault detection method is developed based on this model which is quite robust to uncertainty and results in no false alarm. As soon as a fault is detected, an ANFIS model is trained in online to capture the major behavior of the occurred fault which can be used for fault accommodation. The simulation results understandably demonstrate the capability of the proposed method for accomplishing both tasks appropriately

Connectivity differences in brain networks.

The scenario considered here is one where brain connectivity is represented as a network and an experimenter wishes to assess the evidence for an experimental effect at each of the typically thousands of connections comprising the network. To do this, a univariate model is independently fitted to each connection. It would be unwise to declare significance based on an uncorrected threshold of α=0.05, since the expected number of false positives for a network comprising N=90 nodes and N(N-1)/2=4005 connections would be 200. Control of Type I errors over all connections is therefore necessary. The network-based statistic (NBS) and spatial pairwise clustering (SPC) are two distinct methods that have been used to control family-wise errors when assessing the evidence for an experimental effect with mass univariate testing. The basic principle of the NBS and SPC is the same as supra-threshold voxel clustering. Unlike voxel clustering, where the definition of a voxel cluster is unambiguous, 'clusters' formed among supra-threshold connections can be defined in different ways. The NBS defines clusters using the graph theoretical concept of connected components. SPC on the other hand uses a more stringent pairwise clustering concept. The purpose of this article is to compare the pros and cons of the NBS and SPC, provide some guidelines on their practical use and demonstrate their utility using a case study involving neuroimaging data.

Immunoscintigraphy with antigranulocyte monoclonal antibodies for the diagnosis of septic loosening of hip prostheses.

To determine the value of immunoscintigraphy (IS) with antigranulocyte monoclonal antibodies (Mab) in the diagnosis of subacute or chronic infection of hip prostheses, we prospectively studied 57 patients (23 women and 34 men; age 29-92 years, mean 72.7 years) sent to our institution in the past 6 years for clinical suspicion of septic loosening of a hip prosthesis. Nineteen patients had bilateral prostheses and one of them was studied twice. A total of 78 prostheses were examined. All patients had three-phase bone scans followed by IS with technetium-99m antigranulocyte Mab BW 250/183. Intervals between bone scans and IS varied from 2 days to 4 weeks. Final diagnosis was assessed by culture in 48 cases (articular puncture or intraoperative sampling) and by clinical follow-up of at least 8 months in 30 cases. Twelve prostheses were considered septic and 66 non-septic. The overall sensitivity and specificity were 92% and 64% respectively for bone scans, 67% and 75% for IS and 67% and 84% for both modalities together. In three cases, IS was doubtful and the final clinical diagnosis was negative for infection. False-positive results were observed in the presence of massive loosening of the prosthesis or in association with metaplastic peri-articular bone formation. In three of the four false-negative results, infection was proven only after enrichment of the culture, and the bacterium was Staphylococcus epidermidis. In 12/33 (36%) positive bone scans IS allowed the diagnosis of infection to be excluded. Overall accuracy of both modalities together was 81% and the negative predictive value was 93%, which compares favourably with the results reported for other non-invasive methods.

Surgical management of hemorrhage from rupture of the aortic arch.

BACKGROUND: Control of hemorrhage in patients with active bleeding from rupture of the aortic arch is difficult, because of the location of the bleeding and the impossibility of cross-clamping the aorta without interfering with cerebral perfusion. A precise and swift plan of management helped us salvage some patients and prompted us to review our experience. METHODS: Six patients with active bleeding of the aortic arch in the mediastinum and pericardial cavity (5 patients) or left pleural cavity (1 patient), treated between 1992 and 1996, were reviewed. Bleeding was reduced by keeping the mediastinum under local tension (3 patients) or by applying compression on the bleeding site (2 patients), or both (1 patient) while circulatory support, retransfusion of aspirated blood, and hypothermia were established. The diseased aortic arch was replaced during deep hypothermic circulatory arrest, which ranged from 25 to 40 minutes. In 3 patients, the brain was further protected by retrograde (2 patients) or antegrade (1 patient) cerebral perfusion. RESULTS: Hemorrhage from the aortic arch was controlled in all patients. Two patients died postoperatively, one of respiratory failure and the other of abdominal sepsis. Recovery of neurologic function was assessed and complete in all patients. The 4 survivors are well 8 to 49 months after operation. CONCLUSIONS: An approach relying on local tamponade to reduce bleeding, rapid establishment of circulatory support and hypothermia, retransfusion of aspirated blood, and swift repair of the aortic arch under circulatory arrest allows salvage of patients with active bleeding from an aortic arch rupture.

FGF21 signalling pathway and metabolic traits - genetic association analysis.

Fibroblast growth factor 21 (FGF21) is a novel master regulator of metabolic profile. The biological actions of FGF21 are elicited upon its klotho beta (KLB)-facilitated binding to FGF receptor 1 (FGFR1), FGFR2 and FGFR3. We hypothesised that common polymorphisms in the FGF21 signalling pathway may be associated with metabolic risk. At the screening stage, we examined associations between 63 common single-nucleotide polymorphisms (SNPs) in five genes of this pathway (FGF21, KLB, FGFR1, FGFR2, FGFR3) and four metabolic phenotypes (LDL cholesterol - LDL-C, HDL-cholesterol - HDL-C, triglycerides and body mass index) in 629 individuals from Silesian Hypertension Study (SHS). Replication analyses were performed in 5478 unrelated individuals of the Swiss CoLaus cohort (imputed genotypes) and in 3030 directly genotyped individuals of the German Myocardial Infarction Family Study (GerMIFS). Of 54 SNPs that met quality control criteria after genotyping in SHS, 4 (rs4733946 and rs7012413 in FGFR1; rs2071616 in FGFR2 and rs7670903 in KLB) showed suggestive association with LDL-C (P=0.0006, P=0.0013, P=0.0055, P=0.011, respectively) and 1 (rs2608819 in KLB) was associated with body mass index (P=0.011); all with false discovery rate q<0.5. Of these, only one FGFR2 polymorphism (rs2071616) showed replicated association with LDL-C in both CoLaus (P=0.009) and men from GerMIFS (P=0.017). The direction of allelic effect of rs2071616 upon LDL-C was consistent in all examined populations. These data show that common genetic variations in FGFR2 may be associated with LDL-C in subjects of white European ancestry.

Quantification of 4 antidepressants and a metabolite by LC-MS for therapeutic drug monitoring.

A liquid chromatography method coupled to mass spectrometry was developed for the quantification of bupropion, its metabolite hydroxy-bupropion, moclobemide, reboxetine and trazodone in human plasma. The validation of the analytical procedure was assessed according to Société Française des Sciences et Techniques Pharmaceutiques and the latest Food and Drug Administration guidelines. The sample preparation was performed with 0.5mL of plasma extracted on a cation-exchange solid phase 96-well plate. The separation was achieved in 14min on a C18 XBridge column (2.1mm×100mm, 3.5μm) using a 50mM ammonium acetate pH 9/acetonitrile mobile phase in gradient mode. The compounds of interest were analysed in the single ion monitoring mode on a single quadrupole mass spectrometer working in positive electrospray ionisation mode. Two ions were selected per molecule to increase the number of identification points and to avoid as much as possible any false positives. Since selectivity is always a critical point for routine therapeutic drug monitoring, more than sixty common comedications for the psychiatric population were tested. For each analyte, the analytical procedure was validated to cover the common range of concentrations measured in plasma samples: 1-400ng/mL for reboxetine and bupropion, 2-2000ng/mL for hydroxy-bupropion, moclobemide, and trazodone. For all investigated compounds, reliable performance in terms of accuracy, precision, trueness, recovery, selectivity and stability was obtained. One year after its implementation in a routine process, this method demonstrated a high robustness with accurate values over the wide concentration range commonly observed among a psychiatric population.

Comparativecost-effectivenessanalyses of cardiacmagneticresonanceimaging versus invasive coronary angiography combined with fractional flow reserve testing to diagnose ischemia in coronary artery disease

Introduction: According to guidelines, patients with coronary artery disease (CAD) should undergo revascularization if myocardial ischemia is present. While coronary angiography (CXA) allows the morphological assessment of CAD, the fractional flow reserve (FFR) has proved to be a complementary invasive test to assess the functional significance of CAD, i.e. to detect ischemia. Perfusion Cardiac Magnetic Resonance (CMR) has turned out to be a robust non-invasive technique to assess myocardial ischemia. The objective: is to compare the cost-effectiveness ratio - defined as the costs per patient correctly diagnosed - of two algorithms used to diagnose hemodynamically significant CAD in relation to the pretest likelihood of CAD: 1) aCMRto assess ischemia before referring positive patients to CXA (CMR + CXA), 2) a CXA in all patients combined with a FFR test in patients with angiographically positive stenoses (CXA + FFR). Methods: The costs, evaluated from the health care system perspective in the Swiss, German, the United Kingdom (UK) and the United States (US) contexts, included public prices of the different tests considered as outpatient procedures, complications' costs and costs induced by diagnosis errors (false negative). The effectiveness criterion wasthe ability to accurately identify apatient with significantCAD.Test performancesused in the model were based on the clinical literature. Using a mathematical model, we compared the cost-effectiveness ratio for both algorithms for hypothetical patient cohorts with different pretest likelihood of CAD. Results: The cost-effectiveness ratio decreased hyperbolically with increasing pretest likelihood of CAD for both strategies. CMR + CXA and CXA + FFR were equally costeffective at a pretest likelihood of CAD of 62% in Switzerland, 67% in Germany, 83% in the UK and 84% in the US with costs of CHF 5'794, Euros 1'472, £ 2'685 and $ 2'126 per patient correctly diagnosed. Below these thresholds, CMR + CXA showed lower costs per patient correctly diagnosed than CXA + FFR. Implications for the health care system/professionals/patients/society These results facilitate decision making for the clinical use of new generations of imaging procedures to detect ischemia. They show to what extent the cost-effectiveness to diagnose CAD depends on the prevalence of the disease.

Diagnostic Accuracy of (18)F-FDG-PET and PET/CT in the Differential Diagnosis between Malignant and Benign Pleural Lesions: A Systematic Review and Meta-Analysis.

RATIONALE AND OBJECTIVES: To systematically review and meta-analyze published data about the diagnostic accuracy of fluorine-18-fluorodeoxyglucose ((18)F-FDG) positron emission tomography (PET) and PET/computed tomography (CT) in the differential diagnosis between malignant and benign pleural lesions. METHODS AND MATERIALS: A comprehensive literature search of studies published through June 2013 regarding the diagnostic performance of (18)F-FDG-PET and PET/CT in the differential diagnosis of pleural lesions was carried out. All retrieved studies were reviewed and qualitatively analyzed. Pooled sensitivity, specificity, positive and negative likelihood ratio (LR+ and LR-) and diagnostic odds ratio (DOR) of (18)F-FDG-PET or PET/CT in the differential diagnosis of pleural lesions on a per-patient-based analysis were calculated. The area under the summary receiver operating characteristic curve (AUC) was calculated to measure the accuracy of these methods. Subanalyses considering device used (PET or PET/CT) were performed. RESULTS: Sixteen studies including 745 patients were included in the systematic review. The meta-analysis of 11 selected studies provided the following results: sensitivity 95% (95% confidence interval [95%CI]: 92-97%), specificity 82% (95%CI: 76-88%), LR+ 5.3 (95%CI: 2.4-11.8), LR- 0.09 (95%CI: 0.05-0.14), DOR 74 (95%CI: 34-161). The AUC was 0.95. No significant improvement of the diagnostic accuracy considering PET/CT studies only was found. CONCLUSIONS: (18)F-FDG-PET and PET/CT demonstrated to be accurate diagnostic imaging methods in the differential diagnosis between malignant and benign pleural lesions; nevertheless, possible sources of false-negative and false-positive results should be kept in mind.

Bodily perspective taking goes social: the role of personal, interpersonal, and intercultural factors

Mentally placing the self in the physical position of another person might engage social perspective taking because participants have to match their own position with that of another. We investigated the influence of personal (sex), interpersonal (siblings, parental marital status), and cultural (individualistic, collectivistic) factors on individuals' abilities to mentally take the position of front-facing and back-facing figures in an online study (369 participants). Replicating findings from laboratory studies responses were slower for front-facing than back-facing figures. Having siblings, parents' marital status, and cultural background influenced task performance in theoretically predictable ways. The present perspective-taking task is a promising experimental paradigm to assess social perspective taking and one that is free from the response biases inherent in self-report.

Recent human evolution has shaped geographical differences in susceptibility to disease

Background: Searching for associations between genetic variants and complex diseases has been a very active area of research for over two decades. More than 51,000 potential associations have been studied and published, a figure that keeps increasing, especially with the recent explosion of array-based Genome-Wide Association Studies. Even if the number of true associations described so far is high, many of the putative risk variants detected so far have failed to be consistently replicated and are widely considered false positives. Here, we focus on the world-wide patterns of replicability of published association studies.Results: We report three main findings. First, contrary to previous results, genes associated to complex diseases present lower degrees of genetic differentiation among human populations than average genome-wide levels. Second, also contrary to previous results, the differences in replicability of disease associated-loci between Europeans and East Asians are highly correlated with genetic differentiation between these populations. Finally, highly replicated genes present increased levels of high-frequency derived alleles in European and Asian populations when compared to African populations. Conclusions: Our findings highlight the heterogeneous nature of the genetic etiology of complex disease, confirm the importance of the recent evolutionary history of our species in current patterns of disease susceptibility and could cast doubts on the status as false positives of some associations that have failed to replicate across populations.