Laboratoire des applications Thérapeutiques des Ultrasons

Chicago Classification v4.0 (CCv4.0) is the updated classification scheme for esophageal motility disorders using metrics from high-resolution manometry (HRM). Fifty-two diverse international experts separated into seven working subgroups utilized formal validated methodologies over two-years to develop CCv4.0. Key updates in CCv.4.0 consist of a more rigorous and expansive HRM protocol that incorporates supine and upright test positions as well as provocative testing, a refined definition of esophagogastric junction (EGJ) outflow obstruction (EGJOO), more stringent diagnostic criteria for ineffective esophageal motility and description of baseline EGJ metrics. Further, the CCv4.0 sought to define motility disorder diagnoses as conclusive and inconclusive based on associated symptoms, and findings on provocative testing as well as supportive testing with barium esophagram with tablet and/or functional lumen imaging probe. These changes attempt to minimize ambiguity in prior iterations of Chicago Classification and provide more standardized and rigorous criteria for patterns of disorders of peristalsis and obstruction at the EGJ.

The blood-brain barrier (BBB) limits the delivery of systemically administered drugs to the brain. Methods to circumvent the BBB have been developed, but none are used in standard clinical practice. The lack of adoption of existing methods is due to procedural invasiveness, serious adverse effects, and the complications associated with performing such techniques coincident with repeated drug administration, which is customary in chemotherapeutic protocols. Pulsed ultrasound, a method for disrupting the BBB, was shown to effectively increase drug concentrations and to slow tumor growth in preclinical studies. We now report the interim results of an ultrasound dose-escalating phase 1/2a clinical trial using an implantable ultrasound device system, SonoCloud, before treatment with carboplatin in patients with recurrent glioblastoma (GBM). The BBB of each patient was disrupted monthly using pulsed ultrasound in combination with systemically injected microbubbles. Contrast-enhanced magnetic resonance imaging (MRI) indicated that the BBB was disrupted at acoustic pressure levels up to 1.1 megapascals without detectable adverse effects on radiologic (MRI) or clinical examination. Our preliminary findings indicate that repeated opening of the BBB using our pulsed ultrasound system, in combination with systemic microbubble injection, is safe and well tolerated in patients with recurrent GBM and has the potential to optimize chemotherapy delivery in the brain.

BACKGROUND: An international group of experts evaluated and revised recommendations for ambulatory reflux monitoring for the diagnosis of gastro-esophageal reflux disease (GERD). METHODS: Literature search was focused on indications and technical recommendations for GERD testing and phenotypes definitions. Statements were proposed and discussed during several structured meetings. KEY RESULTS: Reflux testing should be performed after cessation of acid suppressive medication in patients with a low likelihood of GERD. In this setting, testing can be either catheter-based or wireless pH-monitoring or pH-impedance monitoring. In patients with a high probability of GERD (esophagitis grade C and D, histology proven Barrett's mucosa >1 cm, peptic stricture, previous positive pH monitoring) and persistent symptoms, pH-impedance monitoring should be performed on treatment. Recommendations are provided for data acquisition and analysis. Esophageal acid exposure is considered as pathological if acid exposure time (AET) is greater than 6% on pH testing. Number of reflux episodes and baseline impedance are exploratory metrics that may complement AET. Positive symptom reflux association is defined as symptom index (SI) >50% or symptom association probability (SAP) >95%. A positive symptom-reflux association in the absence of pathological AET defines hypersensitivity to reflux. CONCLUSIONS AND INFERENCES: The consensus group determined that grade C or D esophagitis, peptic stricture, histology proven Barrett's mucosa >1 cm, and esophageal acid exposure greater >6% are sufficient to define pathological GERD. Further testing should be considered when none of these criteria are fulfilled.

BACKGROUND: High-resolution manometry (HRM) has resulted in new revelations regarding the pathophysiology of gastro-esophageal reflux disease (GERD). The impact of new HRM motor paradigms on reflux burden needs further definition, leading to a modern approach to motor testing in GERD. METHODS: Focused literature searches were conducted, evaluating pathophysiology of GERD with emphasis on HRM. The results were discussed with an international group of experts to develop a consensus on the role of HRM in GERD. A proposed classification system for esophageal motor abnormalities associated with GERD was generated. KEY RESULTS: Physiologic gastro-esophageal reflux is inherent in all humans, resulting from transient lower esophageal sphincter (LES) relaxations that allow venting of gastric air in the form of a belch. In pathological gastro-esophageal reflux, transient LES relaxations are accompanied by reflux of gastric contents. Structural disruption of the esophagogastric junction (EGJ) barrier, and incomplete clearance of the refluxate can contribute to abnormally high esophageal reflux burden that defines GERD. Esophageal HRM localizes the LES for pH and pH-impedance probe placement, and assesses esophageal body peristaltic performance prior to invasive antireflux therapies and antireflux surgery. Furthermore, HRM can assess EGJ and esophageal body mechanisms contributing to reflux, and exclude conditions that mimic GERD. CONCLUSIONS & INFERENCES: Structural and motor EGJ and esophageal processes contribute to the pathophysiology of GERD. A classification scheme is proposed incorporating EGJ and esophageal motor findings, and contraction reserve on provocative tests during HRM.

Faecal incontinence and evacuation disorders are common and substantially impair quality of life. In this Consensus Statement, the authors describe recommended tests for the evaluation of anorectal function and the clinical relevance of these tests in the management of patients to help guide the practising clinician. Faecal incontinence and evacuation disorders are common, impair quality of life and incur substantial economic costs worldwide. As symptoms alone are poor predictors of underlying pathophysiology and aetiology, diagnostic tests of anorectal function could facilitate patient management in those cases that are refractory to conservative therapies. In the past decade, several major technological advances have improved our understanding of anorectal structure, coordination and sensorimotor function. This Consensus Statement provides the reader with an appraisal of the current indications, study performance characteristics, clinical utility, strengths and limitations of the most widely available tests of anorectal structure (ultrasonography and MRI) and function (anorectal manometry, neurophysiological investigations, rectal distension techniques and tests of evacuation, including defecography). Additionally, this article provides our consensus on the clinical relevance of these tests.

BACKGROUND: Criteria for transient lower esophageal sphincter relaxations (TLESRs) are well-defined for Dentsleeve manometry. As high-resolution manometry (HRM) is now the gold standard to assess esophageal motility, our aim was to propose a consensus definition of TLESRs using HRM. METHODS: Postprandial esophageal HRM combined with impedance was performed in 10 patients with gastroesophageal reflux disease. Transient lower esophageal sphincter relaxations identification was performed by 17 experts using a Delphi process. Four investigators then characterized TLESR candidates that achieved 100% agreement (TLESR events) and those that achieved less than 25% agreement (non-events) after the third round. Logistic regression and decision tree analysis were used to define optimal diagnostic criteria. KEY RESULTS: All diagnostic criteria were more frequently encountered in the 57 TLESR events than in the 52 non-events. Crural diaphragm (CD) inhibition and LES relaxation duration >10 seconds had the highest predictive value to identify TLESR. Based on decision tree analysis, reflux on impedance, esophageal shortening, common cavity, upper esophageal sphincter relaxation without swallow and secondary peristalsis were alternate diagnostic criteria. CONCLUSION & INFERENCES: Using HRM, TLESR might be defined as LES relaxation occurring in absence of swallowing, lasting more than 10 seconds and associated with CD inhibition.

A bio-acoustic levitational assembly method for engineering of multilayered, 3D brainlike constructs is presented. Acoustic radiation forces are used to levitate neuroprogenitors derived from human embryonic stem cells in 3D multilayered fibrin tissue constructs. The neuro-progenitor cells are subsequently differentiated in neural cells, resulting in a 3D neuronal construct with inter and intralayer neurite elongations. As a service to our authors and readers, this journal provides supporting information supplied by the authors. Such materials are peer reviewed and may be re-organized for online delivery, but are not copy-edited or typeset. Technical support issues arising from supporting information (other than missing files) should be addressed to the authors. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

This study evaluated a computer-assisted diagnosis (CADx) system for determining a likelihood measure of prostate cancer presence in the peripheral zone (PZ) based on multiparametric magnetic resonance (MR) imaging, including T2-weighted, diffusion-weighted and dynamic contrast-enhanced MRI at 1.5 T. Based on a feature set derived from grey-level images, including first-order statistics, Haralick features, gradient features, semi-quantitative and quantitative (pharmacokinetic modelling) dynamic parameters, four kinds of classifiers were trained and compared: nonlinear support vector machine (SVM), linear discriminant analysis, k-nearest neighbours and naïve Bayes classifiers. A set of feature selection methods based on t-test, mutual information and minimum-redundancy-maximum-relevancy criteria were also compared. The aim was to discriminate between the relevant features as well as to create an efficient classifier using these features. The diagnostic performances of these different CADx schemes were evaluated based on a receiver operating characteristic (ROC) curve analysis. The evaluation database consisted of 30 sets of multiparametric MR images acquired from radical prostatectomy patients. Using histologic sections as the gold standard, both cancer and nonmalignant (but suspicious) tissues were annotated in consensus on all MR images by two radiologists, a histopathologist and a researcher. Benign tissue regions of interest (ROIs) were also delineated in the remaining prostate PZ. This resulted in a series of 42 cancer ROIs, 49 benign but suspicious ROIs and 124 nonsuspicious benign ROIs. From the outputs of all evaluated feature selection methods on the test bench, a restrictive set of about 15 highly informative features coming from all MR sequences was discriminated, thus confirming the validity of the multiparametric approach. Quantitative evaluation of the diagnostic performance yielded a maximal area under the ROC curve (AUC) of 0.89 (0.81-0.94) for the discrimination of the malignant versus nonmalignant tissues and 0.82 (0.73-0.90) for the discrimination of the malignant versus suspicious tissues when combining the t-test feature selection approach with a SVM classifier. A preliminary comparison showed that the optimal CADx scheme mimicked, in terms of AUC, the human experts in differentiating malignant from suspicious tissues, thus demonstrating its potential for assisting cancer identification in the PZ.

Up to 40% of patients with symptoms suspicious of gastroesophageal reflux disease (GERD) do not respond completely to proton pump inhibitor (PPI) therapy. The term "refractory GERD" has been used loosely in the literature. A distinction should be made between refractory symptoms (ie, symptoms may or may not be GERD-related), refractory GERD symptoms (ie, persisting symptoms in patients with proven GERD, regardless of relationship to ongoing reflux), and refractory GERD (ie, objective evidence of GERD despite adequate medical management). The present ESNM/ANMS consensus paper proposes use the term "refractory GERD symptoms" only in patients with persisting symptoms and previously proven GERD by either endoscopy or esophageal pH monitoring. Even in this context, symptoms may or may not be reflux related. Objective evaluation, including endoscopy and esophageal physiologic testing, is requisite to provide insights into mechanisms of symptom generation and evidence of true refractory GERD. Some patients may have true ongoing refractory acid or weakly acidic reflux despite PPIs, while others have no evidence of ongoing reflux, and yet others have functional esophageal disorders (overlapping with proven GERD confirmed off therapy). In this context, attention should also be paid to supragastric belching and rumination syndrome, which may be important contributors to refractory symptoms.

OBJECTIVES: High-resolution manometry (HRM) might be superior to conventional manometry (CM) to diagnose esophageal motility disorders. We aimed to compare the diagnosis performed with HRM and CM and confirmed at 6 months in a multicenter randomized trial. METHODS: Patients with unexplained dysphagia were randomized to undergo either CM or HRM. Motility disorders were diagnosed using the Castell and Spechler classification for CM and the Chicago classification for HRM. Diagnosis confirmation was based on clinical outcome and response to treatment after 6-month follow-up. The initial diagnosis and percentage of confirmed diagnoses were compared between the two arms (CM and HRM). RESULTS: In total, 247 patients were randomized and 245 analyzed: 122 in the CM arm and 123 in the HRM arm. A manometric diagnosis was more frequently initially achieved with HRM than with CM (97% vs. 84%; P<0.01). Achalasia was more frequent in the HRM arm (26% vs. 12% in the CM arm; P<0.01) while normal examinations were more frequent in the CM arm (52% vs. 28% in the HRM arm; P<0.05). After follow-up, the initial diagnosis was confirmed in 89% of patients in the HRM arm vs. 81% in the CM arm (P=0.07). Finally, overall procedure tolerance was better with CM than with HRM (P<0.01). CONCLUSIONS: This randomized trial demonstrated an improved diagnostic yield for achalasia with HRM compared with CM. Diagnoses tended to be more frequently confirmed in patients who underwent HRM, suggesting that esophageal motility disorders could be identified earlier with HRM than with CM (ClinicalTrial.gov, NCT01284894).

BACKGROUND: Ineffective esophageal motility (IEM) is a heterogenous minor motility disorder diagnosed when ≥50% ineffective peristaltic sequences (distal contractile integral <450 mm Hg cm s) coexist with normal lower esophageal sphincter relaxation (integrated relaxation pressure < upper limit of normal) on esophageal high-resolution manometry (HRM). Ineffective esophageal motility is not consistently related to disease states or symptoms and may be seen in asymptomatic healthy individuals. PURPOSE: A 1-day symposium of esophageal experts reviewed existing literature on IEM, and this review represents the conclusions from the symposium. Severe IEM (>70% ineffective sequences) is associated with higher esophageal reflux burden, particularly while supine, but milder variants do not progress over time or consistently impact quality of life. Ineffective esophageal motility can be further characterized using provocative maneuvers during HRM, especially multiple rapid swallows, where augmentation of smooth muscle contraction defines contraction reserve. The presence of contraction reserve may predict better prognosis, lesser reflux burden and confidence in a standard fundoplication for surgical management of reflux. Other provocative maneuvers (solid swallows, standardized test meal, rapid drink challenge) are useful to characterize bolus transit in IEM. No effective pharmacotherapy exists, and current managements target symptoms and concurrent reflux. Novel testing modalities (baseline and mucosal impedance, functional lumen imaging probe) show promise in elucidating pathophysiology and stratifying IEM phenotypes. Specific prokinetic agents targeting esophageal smooth muscle need to be developed for precision management.

Focused ultrasound (FUS) with the presence of microbubbles induces blood brain barrier (BBB) opening in targeted areas and facilitates drug delivery. However, recent studies have indicated that FUS-BBB opening with excessive exposure levels may be associated with inflammatory response and cellular/tissue damage. Multiple weekly FUS exposures have been shown to be safe for human subjects. However the effect of more frequent FUS exposures is still unknown. This study examines whether frequent focused ultrasound blood brain barrier opening is associated with aggravated behavioral, histopathologic change or brain tissue damage. Two protocols of focused ultrasound blood brain barrier opening were devised using different microbubble doses (0.15 µl/kg and 0.4 µl/kg). Focused ultrasound exposure at a threshold level of BBB-opening, below-threshold level, or above level for intracerebral hemorrhage were delivered every 2 days. Animal behavioral and physiological changes were examined and recorded. Brain tissue was examined for hemorrhage and apoptosis. Results indicate that frequent exposure of excessive focused ultrasound (1.4 mechanical index) produced minor and short-term behavioral changes despite significant tissue damage, while frequent BBB opening with threshold or below-threshold FUS exposure (0.33-0.8 mechanical index) did not cause behavioral or histological change. Immunofluorescent examination of rat brain tissue indicated that excessive doses of microbubble administration induce an apparent cellular apoptotic response, which may be exacerbated by intracerebral hemorrhage. Experimental results suggest that frequent focused ultrasound blood brain barrier opening with sufficient ultrasound exposure level and a microbubble dose can be safe and pose minimal risk to brain tissue.

BACKGROUND: Genesis of persistent gastro-esophageal reflux symptoms despite proton pump inhibitor (PPI) therapy is not fully understood. We aimed at determining reflux patterns on 24-h pH-impedance monitoring performed on PPI and correlating impedance patterns and symptom occurrence in PPI non-responders. METHODS: Seventy-eight PPI non-responder patients underwent 24-h pH-impedance monitoring on PPI. Reflux impedance characterization included gastric and supragastric belches and proximal extent of reflux. Symptoms were considered associated with reflux if occurring within 5 min after a reflux event. Patients were classified into three groups: persistent acid reflux (acid esophageal exposure [AET] >5% of time), reflux sensitivity (AET <5%, symptom index [SI] ≥50%), and functional symptoms (AET <5%, SI <50%). Dominant impedance pattern was determined for each patient. KEY RESULTS: Seven patients (9%) had persistent acid reflux, 28 (36%) reflux sensitivity, and 43 (55%) functional symptoms. A total of 4296 reflux events were identified (median per patient 45 [range 4-221]). Although liquid reflux was the most common pattern in all groups, patients with reflux sensitivity and functional symptoms had much more variability in their pattern profile with a large proportion being associated with gastric and supragastric belching. Only 417 reflux events (9.7%) were associated with symptoms. Reflux with a supragastric component and proximal extent were more likely to be associated with symptoms. CONCLUSIONS & INFERENCES: The impedance reflux profile in PPI non-responders was heterogeneous and the majority of reflux events were not associated with symptoms. Thus, the treatment of PPI non-responders should focus on mechanisms beyond reflux, such as visceral hypersensitivity and hypervigilance.

Vibro-acoustography method is explored for detecting and imaging brachytherapy metal seeds in gel phantoms. In a previous paper, we have shown that some immersed objects' resonance frequencies could be detected by vibro-acoustography. Here, we use this idea to optimize the vibro-acoustic excitation of two different sized brass seeds implanted in an agar gel phantom. In the experiments, the best excitation vibration frequencies were determined either by calculating fundamental resonance frequencies for each of the seeds or the experimental optimal resonance frequency of the gel. The resulting vibro-acoustography images demonstrate remarkable contrast in acoustic emission amplitude compared with images obtained at nonresonance frequencies. Results suggest the possible application of vibro-acoustography for directing prostate brachytherapy seed implantation treatment.

PURPOSE: To assess the factors influencing multiparametric (MP) magnetic resonance (MR) imaging accuracy in estimating prostate cancer histologic volume (Vh). MATERIALS AND METHODS: A prospective database of 202 patients who underwent MP MR imaging before radical prostatectomy was retrospectively used. Institutional review board approval and informed consent were obtained. Two independent radiologists delineated areas suspicious for cancer on images (T2-weighted, diffusion-weighted, dynamic contrast material-enhanced [DCE] pulse sequences) and scored their degree of suspicion of malignancy by using a five-level Likert score. One pathologist delineated cancers on whole-mount prostatectomy sections and calculated their volume by using digitized planimetry. Volumes of MR true-positive lesions were measured on T2-weighted images (VT2), on ADC maps (VADC), and on DCE images [VDCE]). VT2, VADC, VDCE and the greatest volume determined on images from any of the individual MR pulse sequences (Vmax) were compared with Vh (Bland-Altman analysis). Factors influencing MP MR imaging accuracy, or A, calculated as A = Vmax/Vh, were evaluated using generalized linear mixed models. RESULTS: For both readers, Vh was significantly underestimated with VT2 (P < .0001, both), VADC (P < .0001, both), and VDCE (P = .02 and P = .003, readers 1 and 2, respectively), but not with Vmax (P = .13 and P = .21, readers 1 and 2, respectively). Mean, 25th percentile, and 75th percentile, respectively, for Vmax accuracy were 0.92, 0.54, and 1.85 for reader 1 and 0.95, 0.57, and 1.77 for reader 2. At generalized linear mixed (multivariate) analysis, tumor Likert score (P < .0001), Gleason score (P = .009), and Vh (P < .0001) significantly influenced Vmax accuracy (both readers). This accuracy was good in tumors with a Gleason score of 7 or higher or a Likert score of 5, with a tendency toward underestimation of Vh; accuracy was poor in small (<0.5 cc) or low-grade (Gleason score ≤6) tumors, with a tendency toward overestimation of Vh. CONCLUSION: Vh can be estimated by using Vmax in aggressive tumors or in tumors with high Likert scores.

BACKGROUND: After the golden age of antibiotic discovery, bacterial infections still represent a major challenge for public health worldwide. The biofilm mode of growth is mostly responsible for chronic infections that current therapeutics fail to cure and it is well-established that novel strategies must be investigated. Particulate drug delivery systems are considered as a promising strategy to face issues related to antibiotic treatments in a biofilm context. Particularly, poly-lactic acid (PLA) nanoparticles present a great interest due to their ability to migrate into biofilms thanks to their submicronic size. However, questions still remain unresolved about their mode of action in biofilms depending on their surface properties. In the current study, we have investigated the impact of their surface charge, firstly on their behavior within a bacterial biofilm, and secondly on the antibiotic delivery and the treatment efficacy. RESULTS: Rifampicin-loaded PLA nanoparticles were synthetized by nanoprecipitation and characterized. A high and superficial loading of rifampicin, confirmed by an in silico simulation, enabled to deliver effective antibiotic doses with a two-phase release, appropriate for biofilm-associated treatments. These nanoparticles were functionalized with poly-L-lysine, a cationic peptide, by surface coating inducing charge reversal without altering the other physicochemical properties of these particles. Positively charged nanoparticles were able to interact stronger than negative ones with Staphylococcus aureus, under planktonic and biofilm modes of growth, leading to a slowed particle migration in the biofilm thickness and to an improved retention of these cationic particles in biofilms. While rifampicin was totally ineffective in biofilms after washing, the increased retention capacity of poly-L-lysine-coated rifampicin-loaded PLA nanoparticles has been associated with a better antibiotic efficacy than uncoated negatively charged ones. CONCLUSIONS: Correlating the carrier retention capacity in biofilms with the treatment efficacy, positively charged rifampicin-loaded PLA nanoparticles are therefore proposed as an adapted and promising approach to improve antibiotic delivery in S. aureus biofilms.

Summary Ultrasound examination of the gastric antrum is a non‐invasive tool that allows reliable estimation of gastric contents. We performed this prospective cohort study in non‐elective paediatric surgery to assess whether gastric ultrasound may help to determine the best anaesthetic induction technique, whether rapid sequence or routine. The primary outcome was the reduction of inappropriate induction technique. A pre‐operative clinical assessment was performed by the attending anaesthetist who made a provisional plan for induction. Gastric ultrasound was performed in the semirecumbent and right lateral decubitus positions for a qualitative assessment of gastric contents, using a 0–2 grading scale. A final induction plan was made based on this assessment. Immediately after tracheal intubation, gastric contents were suctioned through a multi‐orifice nasogastric tube; these were defined as above risk threshold for regurgitation and aspiration if there was clear fluid &gt; 0.8 ml.kg −1 , and/or the presence of thick fluid and/or solid particles. Gastric ultrasound was feasible in 130 out of 143 (90%) of children, and led to a change in the planned induction technique in 67 patients: 30 from routine to rapid sequence, and 37 from rapid sequence to routine. An appropriate induction technique was therefore performed in 85% of children, vs. 49% planned after pre‐operative clinical assessment alone (p &lt; 0.00001). Our results suggest that gastric ultrasound is a useful guide to the general anaesthetic induction technique with respect to the risk of pulmonary aspiration, in comparison with pre‐operative clinical assessment alone.

Elasticity is a fundamental cellular property that is related to the anatomy, functionality, and pathological state of cells and tissues. However, current techniques based on cell deformation, atomic force microscopy, or Brillouin scattering are rather slow and do not always accurately represent cell elasticity. Here, we have developed an alternative technique by applying shear wave elastography to the micrometer scale. Elastic waves were mechanically induced in live mammalian oocytes using a vibrating micropipette. These audible frequency waves were observed optically at 200,000 frames per second and tracked with an optical flow algorithm. Whole-cell elasticity was then mapped using an elastography method inspired by the seismology field. Using this approach we show that the elasticity of mouse oocytes is decreased when the oocyte cytoskeleton is disrupted with cytochalasin B. The technique is fast (less than 1 ms for data acquisition), precise (spatial resolution of a few micrometers), able to map internal cell structures, and robust and thus represents a tractable option for interrogating biomechanical properties of diverse cell types.

Current therapies for chronic hepatitis B virus (HBV) infections are effective at decreasing the viral load in serum, but do not lead to viral eradication. Recent studies highlighted the therapeutic or "adjuvant" potential of immune-modulators. Our aim was to explore the direct anti-HBV effect of Toll-Like-Receptors (TLR) agonists in hepatocytes. HBV-infected primary human hepatocytes (PHH) or differentiated HepaRG cells (dHepaRG) were treated with various TLR agonists. Amongst all TLR ligands tested, Pam3CSK4 (TLR1/2-ligand) and poly(I:C)-(HMW) (TLR3/MDA5-ligand) were the best at reducing all HBV parameters. No or little viral rebound was observed after treatment arrest, implying a long-lasting effect on cccDNA. We also tested Riboxxol that features improved TLR3 specificity compared to poly(I:C)-(HMW). This agonist demonstrated a potent antiviral effect in HBV-infected PHH. Whereas, poly(I:C)-(HMW) and Pam3CSK4 mainly induced the expression of classical genes from the interferon or NF-κB pathway respectively, Riboxxol had a mixed phenotype. Moreover, TLR2 and TLR3 ligands can activate hepatocytes and immune cells, as demonstrated by antiviral cytokines produced by stimulated hepatocytes and peripheral blood mononuclear cells. In conclusion, our data highlight the potential of innate immunity activation in the direct control of HBV replication in hepatocytes, and support the development of TLR-based antiviral strategies.

PURPOSE: To assess the impact of a computer-aided diagnosis (CAD) system in the characterization of focal prostate lesions at multiparametric magnetic resonance (MR) imaging. MATERIALS AND METHODS: Formal institutional review board approval was not required. Thirty consecutive 1.5-T multiparametric MR imaging studies (with T2-weighted, diffusion-weighted, and dynamic contrast material-enhanced imaging) obtained before radical prostatectomy in patients between September 2008 and February 2010 were reviewed. Twelve readers assessed the likelihood of malignancy of 88 predefined peripheral zone lesions by using a five-level (level, 0-4) subjective score (SS) in reading session 1. This was repeated 5 weeks later in reading session 2. The CAD results were then disclosed, and in reading session 3, the readers could amend the scores assigned during reading session 2. Diagnostic accuracy was assessed by using a receiver operating characteristic (ROC) regression model and was quantified with the area under the ROC curve (AUC). RESULTS: Mean AUCs were significantly lower for less experienced (<1 year) readers (P < .02 for all sessions). Seven readers improved their performance between reading sessions 1 and 2, and 12 readers improved their performance between sessions 2 and 3. The mean AUCs for reading session 1 (83.0%; 95% confidence interval [CI]: 77.9%, 88.0%) and reading session 2 (84.1%; 95% CI: 78.1%, 88.7%) were not significantly different (P = .76). Although the mean AUC for reading session 3 (87.2%; 95% CI: 81.0%, 92.0%) was higher than that for session 2, the difference was not significant (P = .08). For an SS positivity threshold of 3, the specificity of reading session 2 (79.0%; 95% CI: 71.1%, 86.4%) was not significantly different from that of session 1 (78.7%; 95% CI: 70.5%, 86.8%) but was significantly lower than that of session 3 (86.2%; 95% CI: 77.1%, 93.1%; P < .03). The sensitivity of reading session 2 (68.4%; 95% CI: 57.5%, 77.7%) was significantly higher than that of session 1 (64.0%; 95% CI: 52.9%, 73.9%; P = .003) but was not significantly different from that of session 3 (71.4%; 95% CI: 58.3%, 82.7%). CONCLUSION: A CAD system may improve the characterization of prostate lesions at multiparametric MR imaging by increasing reading specificity.