Echogenicity enhancement by end-fluorinated polylactide perfluorohexane nanocapsules: Towards ultrasound-activable nanosystems

International audienc

Association of Specific Comorbidities with Monosodium Urate Crystal Deposition in Urate-Lowering Therapy-Naive Gout Patients: A Cross-Sectional Dual-Energy Computed Tomography Study.

(1) Background: To determine which factors are associated with the volume of monosodium urate (MSU) crystal deposition quantified by dual-energy computed tomography (DECT) in urate-lowering therapy (ULT)-naive gout patients. (2) Methods: In this multicenter cross-sectional study, DECT scans of knees and feet/ankles were prospectively obtained from ULT-naive gout patients. Demographic, clinical (including gout history and comorbidities), and biological data were collected, and their association with DECT MSU crystal volume was analyzed using bivariate and multivariate analyses. A second bivariate analysis was performed by splitting the dataset depending on an arbitrary threshold of DECT MSU volume (1 cm <sup>3</sup> ). (3) Results: A total of 91 patients were included. In the bivariate analysis, age (p = 0.03), gout duration (p = 0.003), subcutaneous tophi (p = 0.004), hypertension (p = 0.02), diabetes mellitus (p = 0.05), and chronic heart failure (p = 0.03) were associated with the total DECT volume of MSU crystal deposition. In the multivariate analysis, factors associated with DECT MSU volumes ≥1 cm <sup>3</sup> were gout duration (odds ratio (OR) for each 10-year increase 3.15 (1.60; 7.63)), diabetes mellitus (OR 4.75 (1.58; 15.63)), and chronic heart failure (OR 7.82 (2.29; 31.38)). (4) Conclusion: Specific comorbidities, particularly chronic heart failure and diabetes mellitus, are more strongly associated with increased MSU crystal deposition in knees and feet/ankles than gout duration, regardless of serum urate level

Inter and intra-rater reliability of rating criteria for the Floor Sitting Posture Screen

Background: Visual assessment of posture and movement is commonly used by musculoskeletal therapists. Postures have historically been assessed using subjective criteria. Recently, however, a number of new rating protocols have been produced with the aim of enhancing the reliability and objectivity of visual assessments. The Floor Sitting Posture Screen (FSPS), a recently developed visual assessment protocol, could be of clinical value however it is yet to be evaluated in terms of inter and intrarater reliability. The Aims of this study were to evaluate the level of inter- and intrarater reliability while using the FSPS. Methods: A blinded test-retest design was used to examine the level of inter- and intra-rater reliability while using the FSPS. Inter-rater reliability was investigated by comparing results of 12 raters (n=11 senior osteopathy students; n=1 osteopath) while rating pictures of 7 subjects (n=5female; n=2 male). The intra-rater reliability was investigated by having raters rate images of 7 subjects (female n=5) on two occasions one week apart. Results: Inter-rater reliability of each criterion (n=17) of the FSPS ranged from Poor to Good. The majority of the criterion (n=11) demonstrated Moderate to Good interrater reliability, with only one criterion demonstrating poor reliability. Intra-rater reliability of individual criterion could not be calculated using Cohen’s Kappa, due to the sample size and the homogeneity of raw data. However, intra-rater percentages of agreement were above 81%for 10 of the 12 raters. The ICC of the combined criteria score of the FSPS was Almost perfect (ICC=0.93; 95% CI= 0.88-0.95). Conclusions: The level of inter and intra-rater reliability and percentage of agreement of some criterion demonstrate promising results. Some criteria need further development before the FSPS can be applied into practice or prior to any further reliability and validity studies

Synthesis of fluorinated polyesters for nanocapsules formulation as ultrasound contrast agents

Nous avons synthétisé des polymères possédant des terminaisons fluorées afin de formuler des nanocapsules comme agents de contraste ultrasonores (ACUs) pour l’imagerie des tumeurs. Ces nanocapsules sont composées d’un cœur de bromure de perfluorooctyle (PFOB), un liquide perfluoré biocompatible et échogène, et d’une coque polymère possédant trois blocs d’affinités différentes. Le bloc hydrophile de polyéthylène glycol (PEG) présent en surface des nanocapsules permet de prolonger leur temps de circulation dans le compartiment sanguin et de favoriser leur accumulation dans les tumeurs par l’effet de perméabilité et de rétention accrue. Le bloc hydrophobe de polylactide (PLA) permet de générer une coque dégradable plus stable que les membranes de lipides ou de tensioactifs qui composent les ACUs utilisés en clinique. Finalement, la terminaison fluorée permet de favoriser l’ancrage du polymère autour de la goutte de liquide perfluoré et d’augmenter l’échogénicité des nanocapsules. Deux stratégies différentes ont été développées pour introduire ce bloc fluoré. La première consistait à synthétiser un PLA terminé par un chaînon fluoré linéaire court (C3F7 à C13F27) et à le mélanger à un polymère dibloc PLA-PEG pour formuler les nanocapsules. Nous avons montré que l’efficacité d’encapsulation du PFOB augmente avec la longueur de chaîne fluorée jusqu’à C8F17. La deuxième stratégie consistait à synthétiser directement un polymère tribloc composé des trois parties PEG, PLA et fluorée sur la même chaîne, la partie fluorée étant constituée de 4 à 15 chaînons C8F17 pendants (structure en peigne). Des mesures de tension interfaciale ont montré que ces polymères triblocs s’adsorbent à l’interface PFOB/solvant organique et encapsulent le PFOB plus efficacement que le PLA-PEG non fluoré. La morphologie des capsules est fortement influencée par le nombre de chaînons fluorés présents dans le polymère et par la quantité de polymère utilisée lors de la formulation. Une masse élevée du polymère contenant 15 chaînons fluorés favorisera ainsi la formation de nanocapsules possédant plusieurs cœurs de PFOB. La diminution de la quantité de polymère fluoré a finalement permis de produire des capsules avec un seul cœur, une coque fine, et de forme légèrement ellipsoïdale. Ces capsules diffusent les ultrasons plus efficacement que les capsules de PLA-PEG non fluoré. Alors que la présence de chaînes de PEG atténue considérablement la réponse acoustique des capsules, l’addition des chaînons fluorés permet de contrebalancer cet effet. Cette amélioration provient de plusieurs paramètres : l’augmentation de la quantité de PFOB encapsulé, l’augmentation de la densité de la capsule, et la diminution de l’épaisseur de la coque des capsules. Par ailleurs, les polymères fluorés et leurs produits de dégradation n’induisent pas de cytotoxicité in vitro comparé à leurs analogues non fluorés. Ces nanocapsules apparaissent donc comme des agents de contraste prometteurs pour permettre de mieux visualiser les tumeurs par échographie.We have synthesized polymers with fluorinated end chains to formulate nanocapsules as ultrasound contrast agents (UCAs) for tumor imaging. These nanocapsules are composed of a core of perfluorooctyl bromide (PFOB), a biocompatible and echogenic perfluorinated liquid, and a polymeric shell made of three blocks of different affinities. The hydrophilic block of poly(ethylene glycol) (PEG) at the surface of the nanocapsules allows increasing their circulation time in the blood and promoting their accumulation into tumors by the enhanced permeation and retention effect. The hydrophobic block of polylactide (PLA) allows generating a degradable shell with higher stability as compared to the surfactant- and lipid-based membranes of commercialized UCAs. Finally, the fluorinated block favors the wetting of the polymer around the perfluorinated liquid and improves the nanocapsules echogenicity. Two different strategies have been developed to introduce this fluorinated part. The first one consisted in synthesizing a PLA terminated by a short linear fluorinated chain (from C3F7 to C13F27) and mixing it with a PLA-PEG diblock polymer to formulate the nanocapsules. The encapsulation efficiency of PFOB was found to increase with the fluorinated chain length up to C8F17. The second strategy consisted in synthesizing directly a triblock polymer composed of the three parts (PEG, PLA and fluorinated) on the same chain, the fluorinated part consisting of 4 to 15 pendant C8F17 chains (with a comb-like structure). Interfacial tension measurements showed that these triblock polymers adsorb at the PFOB/organic solvent interface and encapsulate PFOB more efficiently than non-fluorinated PLA-PEG. The capsules morphology was strongly influenced by the number of fluorinated chains and the amount of polymer used for formulation. Formulation with a high quantity of the polymer containing 15 fluorinated pendants thus favored the formation of nanocapsules with several PFOB cores. Decreasing the fluorinated polymer quantity then allowed producing capsules with a single core, a thin shell, and a slightly ellipsoidal shape. These capsules were more efficient ultrasound scatterers than non-fluorinated PLA-PEG capsules. While the presence of PEG chains considerably attenuates the capsules acoustic response, addition of fluorinated chains seems to counterbalance this effect. Such improvement arises from several contributions: a higher encapsulated PFOB content, a higher density due to the presence of fluorinated chains, and a lower shell thickness. Furthermore, the fluorinated polymers and their degradation products did not induce any in vitro cytotoxicity as compared to their non-fluorinated analogues. These nanocapsules therefore appear as promising UCAs for tumor imaging

Synthèse de polyesters fluorés pour la formulation de nanocapsules comme agents de contraste ultrasonores

We have synthesized polymers with fluorinated end chains to formulate nanocapsules as ultrasound contrast agents (UCAs) for tumor imaging. These nanocapsules are composed of a core of perfluorooctyl bromide (PFOB), a biocompatible and echogenic perfluorinated liquid, and a polymeric shell made of three blocks of different affinities. The hydrophilic block of poly(ethylene glycol) (PEG) at the surface of the nanocapsules allows increasing their circulation time in the blood and promoting their accumulation into tumors by the enhanced permeation and retention effect. The hydrophobic block of polylactide (PLA) allows generating a degradable shell with higher stability as compared to the surfactant- and lipid-based membranes of commercialized UCAs. Finally, the fluorinated block favors the wetting of the polymer around the perfluorinated liquid and improves the nanocapsules echogenicity. Two different strategies have been developed to introduce this fluorinated part. The first one consisted in synthesizing a PLA terminated by a short linear fluorinated chain (from C3F7 to C13F27) and mixing it with a PLA-PEG diblock polymer to formulate the nanocapsules. The encapsulation efficiency of PFOB was found to increase with the fluorinated chain length up to C8F17. The second strategy consisted in synthesizing directly a triblock polymer composed of the three parts (PEG, PLA and fluorinated) on the same chain, the fluorinated part consisting of 4 to 15 pendant C8F17 chains (with a comb-like structure). Interfacial tension measurements showed that these triblock polymers adsorb at the PFOB/organic solvent interface and encapsulate PFOB more efficiently than non-fluorinated PLA-PEG. The capsules morphology was strongly influenced by the number of fluorinated chains and the amount of polymer used for formulation. Formulation with a high quantity of the polymer containing 15 fluorinated pendants thus favored the formation of nanocapsules with several PFOB cores. Decreasing the fluorinated polymer quantity then allowed producing capsules with a single core, a thin shell, and a slightly ellipsoidal shape. These capsules were more efficient ultrasound scatterers than non-fluorinated PLA-PEG capsules. While the presence of PEG chains considerably attenuates the capsules acoustic response, addition of fluorinated chains seems to counterbalance this effect. Such improvement arises from several contributions: a higher encapsulated PFOB content, a higher density due to the presence of fluorinated chains, and a lower shell thickness. Furthermore, the fluorinated polymers and their degradation products did not induce any in vitro cytotoxicity as compared to their non-fluorinated analogues. These nanocapsules therefore appear as promising UCAs for tumor imaging.Nous avons synthétisé des polymères possédant des terminaisons fluorées afin de formuler des nanocapsules comme agents de contraste ultrasonores (ACUs) pour l’imagerie des tumeurs. Ces nanocapsules sont composées d’un cœur de bromure de perfluorooctyle (PFOB), un liquide perfluoré biocompatible et échogène, et d’une coque polymère possédant trois blocs d’affinités différentes. Le bloc hydrophile de polyéthylène glycol (PEG) présent en surface des nanocapsules permet de prolonger leur temps de circulation dans le compartiment sanguin et de favoriser leur accumulation dans les tumeurs par l’effet de perméabilité et de rétention accrue. Le bloc hydrophobe de polylactide (PLA) permet de générer une coque dégradable plus stable que les membranes de lipides ou de tensioactifs qui composent les ACUs utilisés en clinique. Finalement, la terminaison fluorée permet de favoriser l’ancrage du polymère autour de la goutte de liquide perfluoré et d’augmenter l’échogénicité des nanocapsules. Deux stratégies différentes ont été développées pour introduire ce bloc fluoré. La première consistait à synthétiser un PLA terminé par un chaînon fluoré linéaire court (C3F7 à C13F27) et à le mélanger à un polymère dibloc PLA-PEG pour formuler les nanocapsules. Nous avons montré que l’efficacité d’encapsulation du PFOB augmente avec la longueur de chaîne fluorée jusqu’à C8F17. La deuxième stratégie consistait à synthétiser directement un polymère tribloc composé des trois parties PEG, PLA et fluorée sur la même chaîne, la partie fluorée étant constituée de 4 à 15 chaînons C8F17 pendants (structure en peigne). Des mesures de tension interfaciale ont montré que ces polymères triblocs s’adsorbent à l’interface PFOB/solvant organique et encapsulent le PFOB plus efficacement que le PLA-PEG non fluoré. La morphologie des capsules est fortement influencée par le nombre de chaînons fluorés présents dans le polymère et par la quantité de polymère utilisée lors de la formulation. Une masse élevée du polymère contenant 15 chaînons fluorés favorisera ainsi la formation de nanocapsules possédant plusieurs cœurs de PFOB. La diminution de la quantité de polymère fluoré a finalement permis de produire des capsules avec un seul cœur, une coque fine, et de forme légèrement ellipsoïdale. Ces capsules diffusent les ultrasons plus efficacement que les capsules de PLA-PEG non fluoré. Alors que la présence de chaînes de PEG atténue considérablement la réponse acoustique des capsules, l’addition des chaînons fluorés permet de contrebalancer cet effet. Cette amélioration provient de plusieurs paramètres : l’augmentation de la quantité de PFOB encapsulé, l’augmentation de la densité de la capsule, et la diminution de l’épaisseur de la coque des capsules. Par ailleurs, les polymères fluorés et leurs produits de dégradation n’induisent pas de cytotoxicité in vitro comparé à leurs analogues non fluorés. Ces nanocapsules apparaissent donc comme des agents de contraste prometteurs pour permettre de mieux visualiser les tumeurs par échographie

Human Factors Issues of Tcas: a Simulation-Based Study

Since its introduction in the 90’s, TCAS II, presented as a straightforward and very reliable technological tool, has significantly reduced the risk of collision. Paradoxically, the introduction of this system has been accompanied with numerous incidents and one major accident in 2002, mainly due to unclear rules, poor air-ground cooperation and poor human decision. In order to investigate these potential human factors issues, a part-task air-ground simulation was conducted: 10 pilots and 10 controllers were involved in the simulations of 4 scenarios containing TCAS occurrences. Data collected included video camera recordings for behavioral analysis, Heart Rate (HR) for stress evaluation, questionnaires and debriefings for perceived risk levels and situational awareness assessment. The observations and errors were analyzed through the CREAM methodology. The debriefings were led through a self-confrontation technique, together with pilots and controllers. Results show that the simulations of TCAS situations were able to produce a significant physiological stress response with significant increase of HR when a resolution happens. Questionnaires and debriefings show that, in most of the observed cases, aircrew, and controllers are not sharing the same mental picture of the involved traffic and the risk of collision. This raises important issues in terms of cooperation between controllers and aircrews in such demanding occurrences. This should allow identifying risky situations and the related generic causes. The results will be discussed, aiming at a potential improvement of the system, in terms of Human Machine Interface, training and consistency of procedures

Dual-energy computed-tomography-based discrimination between basic calcium phosphate and calcium pyrophosphate crystal deposition in vivo.

Dual-energy computed tomography (DECT) is being considered as a non-invasive diagnostic and characterization tool in calcium crystal-associated arthropathies. Our objective was to assess the potential of DECT in distinguishing between basic calcium phosphate (BCP) and calcium pyrophosphate (CPP) crystal deposition in and around joints in vivo. A total of 13 patients with calcific periarthritis and 11 patients with crystal-proven CPPD were recruited prospectively to undergo DECT scans. Samples harvested from BCP and CPP calcification types were analyzed using Raman spectroscopy and validated against synthetic crystals. Regions of interest were placed in BCP and CPP calcifications, and the following DECT attenuation parameters were obtained: CT numbers (HU) at 80 and 140 kV, dual-energy index (DEI), electron density (Rho), and effective atomic number (Z <sub>eff</sub> ). These DECT attenuation parameters were compared and validated against crystal calibration phantoms at two known equal concentrations. Receiver operating characteristic (ROC) curves were plotted to determine the highest accuracy thresholds for DEI and Z <sub>eff</sub> . Raman spectroscopy enabled chemical fingerprinting of BCP and CPP crystals both in vitro and in vivo. DECT was able to distinguish between HA and CPP in crystal calibration phantoms at two known equal concentrations, most notably by DEI (200 mg/cm <sup>3</sup> : 0.037 ± 0 versus 0.034 ± 0, p = 0.008) and Z <sub>eff</sub> (200 mg /cm <sup>3</sup> : 9.4 ± 0 versus 9.3 ± 0, p = 0.01) analysis. Likewise, BCP calcifications had significantly higher DEI (0.041 ± 0.005 versus 0.034 ± 0.005, p = 0.008) and Z <sub>eff</sub> (9.5 ± 0.2 versus 9.3 ± 0.2, p = 0.03) than CPP crystal deposits with comparable CT numbers in patients. With an area under the ROC curve of 0.83 [best threshold value = 0.0 39, sensitivity = 90. 9% (81.8, 97. 7%), specificity = 64.6% (50.0, 64. 6%)], DEI was the best parameter in distinguishing between BCP and CPP crystal depositions. DECT can help distinguish between crystal-proven BCP and CPP calcification types in vivo and, thus, aid in the diagnosis of challenging clinical cases, and in the characterization of CPP and BCP crystal deposition occurring in osteoarthritis

Are abatacept and tocilizumab intravenous users willing to switch for the subcutaneous route of administration? A questionnaire-based study

International audienceChoosing the subcutaneous (SC) route of administration of abatacept and tocilizumab is more cost-effective than the intravenous (IV) route. The objective of this study was to examine patients' reasons for choosing to keep with their IV infusions or to switch to subcutaneous SC injections. This study was based upon a self-administered questionnaire given to consecutive rheumatoid arthritis patients treated with abatacept or tocilizumab. Patients were asked to express their opinions concerning reasons explaining why they chose to keep the IV route or switch to the SC route. A total of 201 questionnaires completed by 127 patients treated by tocilizumab and 74 by abatacept were analysed. Overall, 45.8% of the patients chose to keep the IV route of administration. Another ongoing SC treatment was noted more often in patients choosing the SC route (15.9 versus 4.3%, p < 0.05). Reasons guiding the choice of the SC route were concerns about repeated hospital day-care (72%), greater autonomy with SC injections (38.7%) and economic considerations (21.5%). Reasons associated with choosing to maintain the IV route were worries about a lack of follow-up (72.1%), the absence of medical assistance during the SC injection (61.2%), maintaining social relationships with other patients developed at the hospital (40.5%), lower frequency of injection (32.9%), fear of adverse events (27.7%) and fear of SC injections (17.9%). Patients reject the SC switch from the IV route of tocilizumab and abatacept mainly because of fears about the unknown SC route, while those who accept it find it more convenient

Cardiovascular events and change in cholesterol levels in patients with rheumatoid arthritis treated with tocilizumab: data from the REGATE Registry.

International audienceObjectives: Rheumatoid arthritis (RA) is responsible for excess mortality mainly due to cardiovascular disease. Studies have found elevated cholesterol levels in RA patients who received tocilizumab (TCZ). We studied the occurrence of major cardiovascular events in RA patients who received TCZ in current practice. We also analysed cholesterol level changes in these patients.Methods: Data were collected from the French REGATE Registry, a multicentre observational study including patients with RA treated with TCZ. All cardiovascular complications were analysed. Changes in cholesterol levels were studied. Factors associated with major adverse cardiac and cerebrovascular events were analysed by multivariate analysis, estimating odds ratios and 95% confidence intervals.Results: During an exposure time of 5591 patient-years (PYs), 35 cardiovascular events occurred in 33 patients, corresponding to an incidence of 0.63/100 PYs. The incidence of ischaemic stroke and cardiac ischaemia was 0.41 and 0.21/100 PYs. Age and personal history of cardiovascular events were identified as risk factors associated with cardiovascular events: OR=1.06 [95% CI 1.02-1.09] and 4.10 [1.90-8.83]. Female sex was a protective factor (OR=0.29 [95% CI 0.14-0.64]). Glucocorticoids may play a role but was not statistically significant. All cholesterol variables were increased in level after the third month of treatment with TCZ, with a 15.4%, 18.9% and 13.4% increase for total cholesterol, LDL-C and HDL-C, at 3 months.Conclusions: In current practice, cardiovascular events occurring under TCZ treatment is in the range of what is expected in RA patients despite a global increase in cholesterol levels