An integrated photoacoustic terahertz gas sensor

An on-chip gas detector that transduces absorbed terahertz light to a mechanical motion using photoacoustics is proposed. The silicon chip confines light in an optical cavity, wherein an acousto-mechanical cavity is housed. The concentration of a trace gas can be determined from the amplitude of a membrane's motion. The simulations presented predict a minimum detectable limit of 1 ppm of methanol for 1 mW of terahertz power and an integration time of 25 ms

Post-traumatic overload or acute syndrome of the os trigonum: a possible cause of posterior ankle impingement

The purpose of this paper is to discuss the post-traumatic overload syndrome of the os trigonum as a possible cause of posterior ankle impingement and hindfoot pain. We have reviewed 19 athletes who were referred to our foot unit between 1995 and 2001 because of posterior ankle pain, and in whom a post-traumatic overload syndrome of os trigonum was diagnosed. All these patients were followed up over a period of 2 years. In 11 cases a chronic repetitive movements in forced plantar flexion was found. In the other eight cases the pain appeared to persist after a standard treatment of an ankle sprain in inversion plantar flexion. The diagnosis was based on clinical history, physical examination and X-rays that revealed a non-fused os trigonum. The confirmation of diagnosis was carried-out injecting local anaesthetic under fluoroscopic control. In all cases a corticosteroid injection as first line treatment was performed. In 6 cases a second injection was necessary to alleviate pain because incomplete recovery with the first injection. Three cases (16%) were recalcitrant to this treatment and in these three cases a surgical excision of the os trigonum was carried out. Our conclusion is that after some chronic athletic activity or an acute ankle sprain the os trigonum, if present, may undergo mechanical overload, remain undisrupted and become painful. Treatment by corticosteroid injection often resolves the proble

Peptide de ciblage de glioblastome adsorbé à la surface de nanocapsules lipidiques : optimisation du procédé et efficacité de ciblage

Contexte et Objectifs. Malgré sa faible prévalence, le glioblastome (GBM), tumeur maligne du cerveau, présente un fort taux de mortalité : médiane de survie de 14 mois avec les traitements standards actuels (résection chirurgicale si elle est possible, suivie d’une radiothérapie et une chimiothérapie adjuvante) (Stupp R et al., N. Engl. J. Med, 2005 ; Stupp R et al., Lancet Oncol., 2009). Les cellules de GBM infiltrées à la périphérie de la résection sont la principale cause des récurrences entrainant le mauvais pronostic des patients. L’objectif d’un des projets soutenu par la Fondation ARC (n° PJA 20161204860), porté par Dr Guillaume Bastiat, est de combiner 2 technologies existantes pour le développement d’un hydrogel de nanocapsules lipidiques (NCLs) (Moysan E et al., Mol. Pharm., 2013 ; Bastiancich C et al., J. Control. Release, 2016) ciblant spécifiquement les cellules de GBM résiduelles, grâce à la présence d’un peptide de ciblage, le NFL-TBS.40-63 (NFL) (Berges R et al., Mol. Ther., 2012 ; Balzeau J. et al., Biomaterials, 2013), à la surface des NCLs. Cet hydrogel de NCLs chargées en actifs anticancéreux, implantable directement après la résection tumorale, comblera le gap thérapeutique entre l’acte chirurgical et l’initiation du traitement standard. L’objectif du présent travail a été de confirmer et d’optimiser l’adsorption du NFL à la surface des NCLs afin qu’elle soit totale, et de vérifier le ciblage spécifique sur différentes lignées cellulaires de GBM. Méthodes. Des NCLs ont été formulées selon un procédé d’inversion de phases largement utilisé par le laboratoire MINT (Heurtault et al., WO2001/064328, 2001), pour aboutir à une nanoparticule de type nano-émulsion à cœur lipophile (Labrafac® WL 1349) stabilisé par un assemblage structuré de tensioactifs (Span® 80 et Kolliphor® HS 15). Dépendamment de la composition initiale, différentes tailles de NCLs ont été réalisées. L’acide stéarique et le bromure de didodécyldiméthylammonium ont été ajoutés jusqu’à 5% (m/mLabrafac) pour modifier la charge de surface des NCLs. La composition en tensioactif Span® 80 a aussi été modifiée pour en étudier son impact. Les NCLs à différentes concentrations (de 0,001 à 275 mg/mL) ont été incubées à température ambiante pendant 12h avec des concentrations fixes de NFL (de 50 à 200 µg/mL). L’adsorption du NFL à la surface des NCLs a été quantifiée en utilisant une méthode de chromatographie d’exclusion stérique qui a l’avantage de s’affranchir de la séparation physique préalable du NFL libre et du NFL adsorbé à la surface des NCLs. Finalement, les meilleurs candidats NCLs (préalablement chargés en sonde fluorescente DiO) ont été testés sur cultures cellulaires de GBM (lignées F98 et RG2), avec différents temps d’incubation (de 1h à 24h) afin de vérifier l’efficacité de ciblage par cytométrie de flux, avec la présence du NFL en surface. Les NCLs sans peptide NFL ont été utilisées comme contrôle.   Résultats. Une nanothèque de NCLs a été formulée avec des caractéristiques physicochimiques parfaitement contrôlées : distribution de taille monomodale et monodisperse (Z-Ave de 30 à 100nm, PdI < 0,1), charge de surface (illustrée par un Pz variant de -10 à +40mV) et une composition en Span® 80 variant de 0 à 15% (m/mNCLs). L’incubation de ces NCLs avec le NFL a permis de mettre en évidence une adsorption totale du NFL sous certaines conditions de concentrations limites. Par exemple, avec des NCLs de 50nm de diamètre, neutres et composées en surface de 15% (m/mNCLs) de Span® 80, l’adsorption du NFL est totale pour un couple de concentrations NFL : NCLs de 100µg/mL : 9mg/mL. Pour des concentrations en NCLs plus importantes, l’adsorption reste totale mais il y a moins de peptide NFL en surface des NCLs. Pour des concentrations en NCLs plus petites, l’adsorption du NFL est partielle : présence de NFL libre et de NFL adsorbé à la surface des NCLs, montrant un effet de saturation de la surface des NCLs. De plus, l’adsorption du NFL dépend de ses propriétés. Ce peptide légèrement cationique va s’adsorber de manière plus efficace sur les NCLs chargées négativement que sur les NCLs neutres. Avec des NCLs chargées positivement, il y a quand même une adsorption totale du NFL mais à des concentrations limites plus importantes, montrant que le processus d’adsorption n’est pas seulement de nature électrostatique. En effet, le NFL est aussi capable de former des liaisons H par la présence du Span® 80 à la surface des NCLs. En effet, une augmentation de la composition en Span® 80 permet une adsorption préférentielle du NFL. Finalement, la taille des NCLs influence également cette adsorption. Le processus dépend de la surface disponible et celle-ci varie avec la modification de la taille des NCLs. Les candidats NCLs présentant une adsorption totale en NFL ont été testés sur culture cellulaire. L’efficacité du ciblage a été montrée, comparativement aux NCLs nues. L’internalisation des NCLs est plus rapide lorsque le peptide NFL est présent en surface. Par exemple, pour des NCLs de 50nm de diamètre, neutres et composées en surface de 15% (m/mNCLs) de Span® 80, l’efficacité de ciblage est de 90% avec le peptide NFL, alors qu’elle est de 57% sans NFL (lignée cellulaire RG2, incubation de 6h). Néanmoins, cette efficacité dépend de différents paramètres : la nature des NCLs, la quantité de NFLs en surface et également la nature des modèles cellulaires (phénotypes différents).  Conclusions et perspectives. Le peptide NFL est capable sous certaines conditions de concentration de s’adsorber de manière totale à la surface des NCLs. Les conditions de concentration sont corrélées à la nature des NCLs et notamment leurs propriétés de surface. Grâce à la présence du NFL en surface des NCLs, le ciblage spécifique de certaines lignées cellulaires de GBM a été montré, restant cependant dépendant de la nature et certainement du phénotype cellulaire. La prochaine étape du projet consiste à optimiser la formulation de l’hydrogel avec les NCLs d’intérêt chargées en actifs thérapeutiques et fonctionnalisées avec le peptide NFL. L’adsorption du NFL sur les NCLs doit rester totale, sans empêcher l’auto-assemblage des NCLs permettant la formation de l’hydrogel. Un suivi de la libération progressive des actifs, des NCLs et du NFL dans un milieu céphalorachidien simulé sera réalisé. Le ciblage spécifique et l’efficacité cytotoxique des NCLs chargées en actif, modifiées en surface par le NFL, et libérées de l’hydrogel seront testés sur des cultures 2D et 3D de cellules de GBM in vitro. Par la suite, un modèle murin de résection de GBM déjà obtenu au laboratoire MINT (Bianco J et al., Neurosci. Methods, 2017 ; Bastiancich C et al., J. Control. Release, 2017) sera utilisé pour établir la preuve de concept de cette nouvelle stratégie thérapeutique dans la prise en charge des GBM opérables

Adaptive model-driven user interface development systems

Adaptive user interfaces (UIs) were introduced to address some of the usability problems that plague many software applications. Model-driven engineering formed the basis for most of the systems targeting the development of such UIs. An overview of these systems is presented and a set of criteria is established to evaluate the strengths and shortcomings of the state-of-the-art, which is categorized under architectures, techniques, and tools. A summary of the evaluation is presented in tables that visually illustrate the fulfillment of each criterion by each system. The evaluation identified several gaps in the existing art and highlighted the areas of promising improvement

Glioblastoma-targeting peptide adsorbed on lipid nanocapsule surface: optimization of the process and targeting efficacy

The current standard of care of glioblastoma (GBM): the highest grade brain tumor is not a curative treatment and does not prevent high patient mortality (median survival of 14 months, and 5-year survival rate lower than 10% (Stupp R et al., N. Engl. J. Med, 2005; Stupp R et al., Lancet Oncol., 2009)). The scientific community must address solutions to these unmet medical and patient needs and opportunities can be found to develop innovative and complementary treatment to the standard therapeutic scheme. The GLIOGEL project (ERA-NET Cofund EuroNanoMed III) focuses on a hydrogel of GBM-targeting, drug-loaded lipid nanocapsules (LNCs). This new drug delivey system will be implantable directly after GBM resection, and will close the treatment gap until Stupp protocol (radiotherapy and/or adjuvant chemotherapy, 4 to 6 weeks after resection). The sustained LNCs release will specifically target the residual infiltrating GBM cells at resection border, main cause of tumor recurrences. The proof of concept of adsorption of a targeting peptide: the NFL-TBS.40-63 (NFL) at LNC surface was already done, with the specific targeting property for GBM cells (Berges R et al., Mol. Ther., 2012 ; Balzeau J. et al., Biomaterials, 2013). So the first part of the project was to confirm and optimize the association NFL-LNCs, and to show correlations regarding NFL and LNC physicochemical properties.   LNCs in suspension with different sizes (from 30 to 100nm), surface charges (positive, neutral and negative) and Span® 80 composition (from 0 to 15% w/wLNCs) have been performed according to a phase inversion process (Heurtault et al., WO2001 / 064328, 2001). Different LNC concentrations (0.001 to 275mg/mL) were incubated at room temperature for 12h with fixed NFL concentrations (50 to 200μg/mL). Free NFL proportions were quantified in the free NFL and NFL-adsorbed LNC mixtures without prior separation, i.e. directly after incubation, to avoid all the bias that can be observed using physical separations such as filtration by centrifugation and dialysis. A Steric Exclusion Chromatography method was developed for this purpose. Due to NFL properties (slightly positively charged and capacity to form H-bond), we showed that the NFL adsorption at LNC surface was enhanced with negatively charged LNCs, and when Span® 80 proportion at LNC surface increase. These results were confirmed using two other methods without prior separation: NMR diffusometry using the diffusion coefficients for both free and adsorbed NFLs, and Fluorescence Correlation Spectroscopy using FITC-labeled NFL. Other protein or peptide-adsorbed nanoparticles could be characterized using these three methods, and the absence of physical separation before the quantification is a real benefit for the accuracy and veracity of data. Finally, the best LNC candidates with total NFL adsorption were tested on a large library of GBM cell lines, with different incubation times in order to verify the targeting efficacy. The LNCs internalization is faster when the NFL is present at their surface. Nevertheless, we observed that the efficiency depends on different parameters: the amount of NFLs at LNC surface and also the cellular models

Variation in care and outcome for fragile hip fracture patients: a European multicentre study benchmarking fulfilment of established quality indicators

PURPOSE Despite the availability of clinical guidelines for hip fracture patients, adherence to these guidelines is challenging, potentially resulting in suboptimal patient care. The goal of this study was (1) to evaluate and benchmark the adherence to recently established quality indicators (QIs), and (2) to study clinical outcomes, in fragile hip fracture patients from different European countries. METHODS This observational, cross-sectional multicenter study was performed in 10 hospitals from 9 European countries including data of 298 consecutive patients. RESULTS A large variation both within and between hospitals were seen regarding adherence to the individual QIs. QIs with the lowest overall adherence rates were the administration of systemic steroids (5.4%) and tranexamic acid (20.1%). Indicators with the highest adherence rates (above 95%) were pre-operative (99.3%) and post-operative haemoglobin level assessment (100%). The overall median time to surgery was 22.6 h (range 15.7-42.5 h). The median LOS was 9.0 days (range 5.0-19.0 days). The most common complications were delirium (23.2%) and postsurgical constipation (25.2%). CONCLUSION The present study shows large variation in the care for fragile patients with hip fractures indicating room for improvement. Therefore, hospitals should invest in benchmarking and knowledge-sharing. Large quality improvement initiatives with longitudinal follow up of both process and outcome indicators should be initiated

Workforce analysis using data mining and linear regression to understand HIV/AIDS prevalence patterns

<p>Abstract</p> <p>Background</p> <p>The achievement of the Millennium Development Goals (MDGs) depends on sufficient supply of health workforce in each country. Although country-level data support this contention, it has been difficult to evaluate health workforce supply and MDG outcomes at the country level. The purpose of the study was to examine the association between the health workforce, particularly the nursing workforce, and the achievement of the MDGs, taking into account other factors known to influence health status, such as socioeconomic indicators.</p> <p>Methods</p> <p>A merged data set that includes country-level MDG outcomes, workforce statistics, and general socioeconomic indicators was utilized for the present study. Data were obtained from the Global Human Resources for Health Atlas 2004, the WHO Statistical Information System (WHOSIS) 2000, UN Fund for Development and Population Assistance (UNFDPA) 2000, the International Council of Nurses "Nursing in the World", and the WHO/UNAIDS database.</p> <p>Results</p> <p>The main factors in understanding HIV/AIDS prevalence rates are physician density followed by female literacy rates and nursing density in the country. Using general linear model approaches, increased physician and nurse density (number of physicians or nurses per population) was associated with lower adult HIV/AIDS prevalence rate, even when controlling for socioeconomic indicators.</p> <p>Conclusion</p> <p>Increased nurse and physician density are associated with improved health outcomes, suggesting that countries aiming to attain the MDGs related to HIV/AIDS would do well to invest in their health workforce. Implications for international and country level policy are discussed.</p

My IoT Puzzle: Debugging IF-THEN Rules Through the Jigsaw Metaphor

End users can nowadays define applications in the format of IF-THEN rules to personalize their IoT devices and online services. Along with the possibility to compose such applications, however, comes the need to debug them, e.g., to avoid unpredictable and dangerous behaviors. In this context, different questions are still unexplored: which visual languages are more appropriate for debugging IF-THEN rules? Which information do end users need to understand, identify, and correct errors? To answer these questions, we first conducted a literature analysis by reviewing previous works on end-user debugging, with the aim of extracting design guidelines. Then, we developed My IoT Puzzle, a tool to compose and debug IF-THEN rules based on the Jigsaw metaphor. My IoT Puzzle interactively assists users in the debugging process with different real-time feedback, and it allows the resolution of conflicts by providing textual and graphical explanations. An exploratory study with 6 participants preliminary confirms the effectiveness of our approach, showing that the usage of the Jigsaw metaphor, along with real-time feedback and explanations, helps users understand and fix conflicts among IF-THEN rules

Assessment of Minimal Residual Disease in Standard-Risk AML

BACKGROUND: Despite the molecular heterogeneity of standard-risk acute myeloid leukemia (AML), treatment decisions are based on a limited number of molecular genetic markers and morphology-based assessment of remission. Sensitive detection of a leukemia-specific marker (e.g., a mutation in the gene encoding nucleophosmin [NPM1]) could improve prognostication by identifying submicroscopic disease during remission. METHODS: We used a reverse-transcriptase quantitative polymerase-chain-reaction assay to detect minimal residual disease in 2569 samples obtained from 346 patients with NPM1-mutated AML who had undergone intensive treatment in the National Cancer Research Institute AML17 trial. We used a custom 51-gene panel to perform targeted sequencing of 223 samples obtained at the time of diagnosis and 49 samples obtained at the time of relapse. Mutations associated with preleukemic clones were tracked by means of digital polymerase chain reaction. RESULTS: Molecular profiling highlighted the complexity of NPM1-mutated AML, with segregation of patients into more than 150 subgroups, thus precluding reliable outcome prediction. The determination of minimal-residual-disease status was more informative. Persistence of NPM1-mutated transcripts in blood was present in 15% of the patients after the second chemotherapy cycle and was associated with a greater risk of relapse after 3 years of follow-up than was an absence of such transcripts (82% vs. 30%; hazard ratio, 4.80; 95% confidence interval [CI], 2.95 to 7.80; P<0.001) and a lower rate of survival (24% vs. 75%; hazard ratio for death, 4.38; 95% CI, 2.57 to 7.47; P<0.001). The presence of minimal residual disease was the only independent prognostic factor for death in multivariate analysis (hazard ratio, 4.84; 95% CI, 2.57 to 9.15; P<0.001). These results were validated in an independent cohort. On sequential monitoring of minimal residual disease, relapse was reliably predicted by a rising level of NPM1-mutated transcripts. Although mutations associated with preleukemic clones remained detectable during ongoing remission after chemotherapy, NPM1 mutations were detected in 69 of 70 patients at the time of relapse and provided a better marker of disease status. CONCLUSIONS: The presence of minimal residual disease, as determined by quantitation of NPM1-mutated transcripts, provided powerful prognostic information independent of other risk factors. (Funded by Bloodwise and the National Institute for Health Research; Current Controlled Trials number, ISRCTN55675535.)

Standardisation and consensus guidelines for minimal residual disease assessment in Philadelphia-positive acute lymphoblastic leukemia (Ph?+?ALL) by real-time quantitative reverse transcriptase PCR of e1a2 BCR-ABL1

Minimal residual disease (MRD) is a powerful prognostic factor in acute lymphoblastic leukemia (ALL) and is used for patient stratification and treatment decisions, but its precise role in Philadelphia chromosome positive ALL is less clear. This uncertainty results largely from methodological differences relating to the use of real-time quantitative PCR (qRT-PCR) to measure BCR-ABL1 transcript levels for MRD analysis. We here describe the first results by the EURO-MRD consortium on standardization of qRT-PCR for the e1a2 BCR-ABL1 transcript in Ph + ALL, designed to overcome the lack of standardisation of laboratory procedures and data interpretation. Standardised use of EAC primer/probe sets and of centrally prepared plasmid standards had the greatest impact on reducing interlaboratory variability. In QC1 the proportion of analyses with BCR-ABL1/ABL1 ratios within half a log difference were 40/67 (60%) and 52/67 (78%) at 10−3 and 36/67 (53%) and 53/67 (79%) at 10−4BCR-ABL1/ABL1. Standardized RNA extraction, cDNA synthesis and cycler platforms did not improve results further, whereas stringent application of technical criteria for assay quality and uniform criteria for data interpretation and reporting were essential. We provide detailed laboratory recommendations for the standardized MRD analysis in routine diagnostic settings and in multicenter clinical trials for Ph + ALL