Sensor Noise in LISA Pathfinder: In-Flight Performance of the Optical Test Mass Readout.

We report on the first subpicometer interferometer flown in space. It was part of ESA's Laser Interferometer Space Antenna (LISA) Pathfinder mission and performed the fundamental measurement of the positional and angular motion of two free-falling test masses. The interferometer worked immediately, stably, and reliably from switch on until the end of the mission with exceptionally low residual noise of 32.0_{-1.7}^{+2.4} fm/sqrt[Hz], significantly better than required. We present an upper limit for the sensor performance at millihertz frequencies and a model for the measured sensitivity above 200 mHz.

Occurrence, prevalence, and explanatory environmental variables of Spirocerca vulpis infestation in the foxes of western Spain.

The main aim of this study was to not only establish the prevalence of the recently described Spirocerca vulpis parasite in the wild-life cycle of carnivores in western Spain but to also elaborate a model to explain the risk of infestation based on 16 topo-climatic and habitat variables. During the period from June 2016 to November 2017, 1644 carcasses of red foxes (Vulpes vulpes) and another 105 wild mammals, legally hunted or killed in car accidents, were analyzed. Parasitic nodules of Spirocerca were found in 6% of the foxes, and the molecular analyses established a homology of our samples with the species S. vulpis. There were no differences in the occurrence of the infestation between sexes, but there were differences in terms of age, such that infestation was proportionally more frequent among young individuals. In terms of temporality, a higher percentage of positive cases was observed during the late-autumn and winter months, especially between December and February. This study provides new data on the factors that predispose S. vulpis infection in the red fox. Model results indicate that a spatial pattern exists in the occurrence and prevalence of this species in the studied area (higher probabilities to the west), and that this pattern seems to mainly be associated with topo-climatic variables.

LISA Pathfinder Performance Confirmed in an Open-Loop Configuration: Results from the Free-Fall Actuation Mode.

We report on the results of the LISA Pathfinder (LPF) free-fall mode experiment, in which the control force needed to compensate the quasistatic differential force acting on two test masses is applied intermittently as a series of "impulse" forces lasting a few seconds and separated by roughly 350 s periods of true free fall. This represents an alternative to the normal LPF mode of operation in which this balancing force is applied continuously, with the advantage that the acceleration noise during free fall is measured in the absence of the actuation force, thus eliminating associated noise and force calibration errors. The differential acceleration noise measurement presented here with the free-fall mode agrees with noise measured with the continuous actuation scheme, representing an important and independent confirmation of the LPF result. An additional measurement with larger actuation forces also shows that the technique can be used to eliminate actuation noise when this is a dominant factor.

Evolution of the use of antioxidants in anti-ageing cosmetics.

OBJECTIVE: Skin health and beauty are a cornerstone of general well-being in humans. Anti-ageing cosmetics are used to provide a healthy and youthful appearance. Among the different cosmetic actives, antioxidants are incorporated in anti-ageing products due to their beneficial effects in preventing and minimizing the signs of skin ageing. This work aims to understand how anti-ageing formulations changed in the past 7 years regarding pure antioxidants composition. METHODS: Data were collected from anti-ageing formulations commercialized in main stores and pharmacies in the Portuguese market. The study started on 2011 and was updated with products launched or whose composition has been renewed on 2013, 2015 or 2018. RESULTS: Ascorbic acid and tocopherol and their derivatives were consistently the most used antioxidants in anti-ageing formulations; followed by niacinamide and retinyl palmitate. Seven ascorbic acid derivatives are currently used in anti-ageing formulations while only three tocopherol derivatives were identified in this study. Several combinations of antioxidants were routinely found, mainly tocopherol (or tocopherol derivatives) with other antioxidants and tocopherol with tocopherol derivatives. We have not identified emerging antioxidants with great impact in anti-ageing formulations even though niacinamide and retinyl palmitate exhibited over 10% more usage in 2018. CONCLUSION: This insight is relevant to the cosmetic industry providing a better understanding of the scientific-based formulation of modern cosmetics and supports the need for innovative antioxidants in anti-ageing cosmetics.

OBJECTIF: La santé de la peau et la beauté constituent la base du bien-être général chez l'homme. Les cosmétiques anti-âge sont utilisés pour donner une apparence saine et jeune. Parmi les différents principes actifs des cosmétiques, des antioxydants sont incorporées dans les produits anti-âge en raison de leur effet bénéfique sur la prévention et la réduction des signes de vieillissement de la peau. Ce travail vise à comprendre comment les formulations anti-âge ont évolué au cours des 7 dernières années au niveau des antioxydants purs composition. MÉTHODES: Les données ont été recueillies sur des formulations anti-âge commercialisées dans les principaux magasins et pharmacies du marché portugais. Cette étude a commencé en 2011 et a été mise à jour avec des produits mis sur le marché ou dont la composition a été renouvelée en 2013, 2015 ou 2018. RÉSULTATS: L'acide ascorbique et tocophérol et leurs dérivés sont systématiquement les antioxydants les plus utilisés dans les formulations anti-âge; ils sont suivis de la niacinamide et du palmitate de rétinol. Sept dérivés d'acide ascorbique sont actuellement utilisés pour lutter contre le vieillissement, tandis que seulement trois dérivés de tocophérol ont été identifiés dans cette étude. Plusieurs combinaisons d'antioxydants ont été systématiquement observées, principalement le tocophérol ou les dérivés de tocophérol avec d'autres antioxydants, et le tocophérol avec des dérivés de tocophérol. Nous n'avons pas identifié de nouveaux antioxydants présentant un impact majeur dans les formulations anti-âge, même si la niacinamide et le palmitate de rétinol ont vu leur utilisation augmenter de 10% en 2018. CONCLUSION: Cette perspective est pertinente pour le secteur des cosmétiques. Elle permet de mieux comprendre la formulation scientifique des cosmétiques modernes et confirme le besoin d'innover au niveau des antioxydants utilisés dans les produits anti-âge. Les cosmétiques anti-âge sont utilisés pour donner une apparence saine et jeune. Parmi les différents actifs cosmétiques, les antioxydants sont incorporés dans les produits anti-âge en raison de leurs effets bénéfiques dans la prévention et la réduction des signes du vieillissement cutané. Ce travail vise à comprendre comment les formulations anti - vieillissement ont changé au cours des 7 dernières années en ce qui concerne la composition en antioxydants purs.

Alginate microparticles as carriers for the UV filter 2-ethylhexyl 4-methoxycinnamate: Influence on photostability.

OBJECTIVE: The organic ultraviolet UVB filter 2-ethylhexyl 4-methoxycinnamate (EHMC) was encapsulated in microparticles (MPs) of sodium alginate and co-loaded with vitamin E (Vit.E) by an extrusion process using an aerodynamically assisted jetting (AAJ) methodology. The aim was to assess the effect of encapsulation concerning UVB filter release from the MPs and its photochemical stability. METHODS: The EHMC photostability was analysed by exposing the samples (both MPs in aqueous dispersion and incorporated in a cream preparation) during 1 h to simulated solar light. For the MPs (empty-MP, EHMC-MP and EHMC + Vit.E-MP), the morphology and size were characterized; while in the case of the encapsulated samples, the amount of EHMC-loading was determined. The release of EHMC was evaluated by adding EHMC-MP or EHMC + Vit.E-MP to 65% ethanol in water under mechanical stirring at 32°C. RESULTS: All MPs showed a homogeneous size distribution with a median of 90.5 ± 2.5 µm for EHMC-MP and 70.4 ± 1.14 µm for EHMC + Vit.E-MP. The encapsulation efficiency was 92.9% and 99.4% for EHMC-MP and EHMC + Vit.E-MP, respectively. The observed release from the MPs was lower than the dissolution of the pure UV filter. EHMC-MP and EHMC + Vit.E-MP were successfully incorporated into a cream formulation, with no evidence of phase separation or colour modification. Upon simulated light exposure, the photoisomerization/phototransformation of EHMC encapsulated in MPs and Vit.E-MP decreased as compared to free EHMC, both in aqueous dispersion and as a cream. The conformational ratio of the isomers (Z-/E-EHMC) was found to be the lowest in the presence of Vit.E. CONCLUSION: This work demonstrates that use of these alginate microparticulate carriers could enhance the effectiveness of sunscreen preparations containing this UVB filter.

OBJECTIF: Le filtre ultraviolet organique D'UVB 2-éthylhexyl 4-methoxycinnamate (EHMC) a été encapsulé dans des microparticules (MPs) d'alginate de sodium et co-chargé avec la vitamine E (Vit.E) par un processus d'extrusion utilisant une méthode de jet assisté aérodynamique (AAJ). L'objectif était d'évaluer l'effet de l'encapsulation concernant la libération du filtre UVB par les MPs et sa stabilité photochimique. MÉTHODES: La photostabilité EHMC a été analysée en exposant les échantillons (les deux MPs en dispersion aqueuse et incorporés dans une préparation de type crème) pendant 1 h à la lumière solaire simulée. Pour les MPs (MP-vide, EHMC-MP et EHMC - Vit.E-MP), la morphologie et la taille ont été caractérisées; tandis que dans le cas des échantillons encapsulés, la quantité de charge EHMC a été déterminée. Le relargage de l'EHMC a été évalué en ajoutant EHMC-MP ou EHMC - Vit.E-MP à 65% d'éthanol dans l'eau sous agitation mécanique à 32°C. RÉSULTATS: Tous les MP ont montré une distribution homogène de taille avec une médiane de 90,5 +- 2,5 µm pour EHMC-MP et de 70,4 +- 1,14 µm pour l'EHMC et Vit.E-MP. L'efficacité de l'encapsulation était de 92,9 % et 99,4 % pour EHMC-MP et EHMC - Vit.E-MP, respectivement. Le relargage observé des MPs était inférieur à la dissolution du filtre UV pur. EHMC-MP et EHMC - Vit.E-MP ont été incorporés avec succès dans une formulation de crème, sans aucune preuve de séparation de phase ou de modification des couleurs. Après exposition à la lumière simulée, la photoiomérisation/phototransformation de l'EHMC encapsulée dans les MPs et Vit.E-MP a diminué par rapport à l'EHMC libre, à la fois dans la dispersion aqueuse et la crème. Le rapport conformationnel des isomères (Z-/E-EHMC) s'est avéré le plus bas en présence de Vit.E.

Mechanical Properties of Topical Anti-Psoriatic Medicines: Implications for Patient Satisfaction with Treatment.

Different types of topical preparations are available as anti-psoriatic medicines, semisolid formulations being the preferred dosage forms for the treatment of body lesions. The mechanical characterization of these semisolid formulations is seldom reported, although mechanical features have been recognized to play an important role in treatment acceptability and adherence. The aim of this study was to characterize the mechanical properties of semisolid topical formulations commercially available for psoriasis treatment. One complementary aim was to evaluate patient satisfaction with topical treatment and discuss the results according to the mechanical features of the dosage form. Eight ointments (O 1-8), five creams (C 1-5), one oleogel (G1), and one excipient (E1-petrolatum) were characterized for textural properties (spreadability and penetration tests) and flow behavior. Power law model was fitted to the results. A questionnaire for the assessment of satisfaction with topical medicines used for psoriasis treatment over 6 months was developed and applied to 79 psoriasis patients. All the tested formulations presented a shear-thinning behavior with power law indexes (n) lower than 1. Ointments were distinct from the other dosage forms, since they presented higher consistency coefficients (K), firmness, and adhesiveness and this was evidenced by hierarchical cluster analysis, which identified two clusters based on the mechanical properties. Cluster 1 included the ointments and petrolatum and the cluster 2 enclosed the creams and the gel. The clusters were associated with several attributes classified by patients as analyzed with Fisher's exact test. In all cases, higher satisfaction was observed for cluster 2. The knowledge obtained regarding the influence of the dosage form on the degree of satisfaction with the treatment could be helpful in supporting the selection of the dosage form in clinical practice and thus improve treatment adherence and clinical outcomes. The differences observed between the mechanical properties of the formulations studied may be also relevant to the industry, as guidance to the development of new medicines.

Beyond the Required LISA Free-Fall Performance: New LISA Pathfinder Results down to 20 µHz.

In the months since the publication of the first results, the noise performance of LISA Pathfinder has improved because of reduced Brownian noise due to the continued decrease in pressure around the test masses, from a better correction of noninertial effects, and from a better calibration of the electrostatic force actuation. In addition, the availability of numerous long noise measurement runs, during which no perturbation is purposely applied to the test masses, has allowed the measurement of noise with good statistics down to 20 µHz. The Letter presents the measured differential acceleration noise figure, which is at (1.74±0.05) fm s^{-2}/sqrt[Hz] above 2 mHz and (6±1)×10 fm s^{-2}/sqrt[Hz] at 20 µHz, and discusses the physical sources for the measured noise. This performance provides an experimental benchmark demonstrating the ability to realize the low-frequency science potential of the LISA mission, recently selected by the European Space Agency.

Comparison between sensory and instrumental characterization of topical formulations: impact of thickening agents.

OBJECTIVE: Sensorial properties of cutaneous formulations are important in determining their acceptability by consumers. However, sensorial analysis is time-consuming and requires an available panel of trained assessors. Thus, this article aimed to study the impact of thickening agents on mechanical properties of creams and investigate how these measurements could correlate the sensory attributes using a combined instrumental-sensorial approach. METHODS: For this purpose, eight semisolid formulations were prepared, containing in their composition different thickening agents at different concentrations. These formulations were firstly microscopically observed and then assayed through textural, rheological and spreadability measurements. Textural characterization and rheological characterization were performed during six months to assess the physical stability of the studied formulations. Finally, six sensory attributes, namely firmness, adhesiveness, cohesiveness, spreadability, consistency and adhesiveness post-application, were tested by a trained panel. RESULTS: It was observed that thickening agents influence the microstructure of semisolid emulsions and also their mechanical properties. In general, an increase in the concentration of thickening agents improves the physical stability of formulations over time. Besides, textural parameters (firmness and adhesiveness), viscosity and difficulty to spread also increase. A good correlation between mechanical characterization and sensorial analysis was verified, mainly for spreadability properties. CONCLUSION: With the obtained results, it is possible to conclude that the proposed methods for mechanical characterization can be correlated with sensorial perception obtained from volunteers, representing a faster and less expensive alternative than sensory analysis.

A founder EIF2AK4 mutation causes an aggressive form of pulmonary arterial hypertension in Iberian Gypsies.

Pulmonary arterial hypertension (PAH) is a pathological condition characterized by a persistent and progressive elevation of pulmonary vascular resistance with devastating consequences if untreated. In the past recent years, several genes have been related to PAH, however, the molecular defect remains unknown in a significant proportion of patients with familial PAH (∼20%). During the past few years, we have observed that PAH shows a particular behavior in Iberian Gypsies, with more aggressive course and frequently affecting multiple members of the same family. We studied five Gypsy families in whom at least one individual from each family developed a severe form of PAH and in whom no mutation had been identified in the common genes. We applied SNP-array-based homozygosity mapping in three families and obtained, among others, one of which included the gene EIF2AK4, recently reported in patients with PAH from group-1' pulmonary veno-occlusive disease (PVOD) and pulmonary capillary hemangiomatosis (PCH). Subsequently, we sequenced EIF2AK4 and found a homozygous mutation in all five families: c.3344C>T(p.P1115L). The majority of our patients required early lung transplantation. Hence, this mutation appeared with a more severe phenotype than previously reported for other EIF2AK4 mutations. The finding of this novel mutation is important for genetic counseling and calculation of population recurrence risks.

Characterization, sensorial evaluation and moisturizing efficacy of nanolipidgel formulations.

BACKGROUND: Nanostructured lipid carriers (NLC) have been widely studied for cosmetic and dermatological applications due to their favourable properties that include the formation of an occlusive film on the skin surface that reduces the transepidermal water loss (TEWL) and increase in water content in the skin which improves the appearance on healthy human skin and reduces symptoms of some skin disorders like eczema. OBJECTIVE: The main objective of this study was the development of semisolid formulations based NLC with argan oil or jojoba oil as liquid lipids, by addition of Carbopol®934 or Carbopol®980 as gelling agents, followed by comparison between instrumental analysis and sensorial evaluation and in vivo efficacy evaluation. METHODS: Nanostructured lipid carriers dispersions were produced by the ultrasound technique, and to obtain a semisolid formulation, gelling agents were dispersed in the aqueous dispersion. Particle size, polydispersity index and zeta potential were determined. Instrumental characterization was performed by rheological and textural analysis; the sensorial evaluation was also performed. Finally, skin hydration and TEWL were studied by capacitance and evaporimetry evaluation, respectively. RESULTS: Particles showed a nanometric size in all the analysed formulations. All the gels present pseudoplastic behaviour. There is a correspondence between the properties firmness and adhesiveness as determined by textural analysis and the sensory evaluation. The formulations that showed a greater increase in skin hydration also presented appropriate technological and sensorial attributes for skin application. CONCLUSIONS: Nanolipidgel formulations with the addition of humectants are promising systems for cosmetic application with good sensory and instrumental attributes and moisturizing efficacy.

Ecotoxicological heterogeneity in transitional coastal habitats assessed through the integration of biomarkers and sediment-contamination profiles: a case study using a commercial clam.

Transitional waterbodies, such as estuaries, are highly diversified environments with respect to ecology, geophysics, and nature of anthropogenic impacts. This spatial heterogeneity may pose important constraints when developing monitoring programmes for aquatic pollution. The present study compared three distinct coastal ecosystems located in Southern Portugal (subjected to different anthropogenic stressors), namely, two estuaries and a coastal lagoon, through the characterisation of sediment contamination and a biomarker approach to an important commercial clam (Ruditapes decussatus) obtained from local fishing grounds. The results showed high heterogeneity of sediment contamination for both estuaries and a marked distinction between industrially and agriculturally influenced areas as well as between natural and artificialized sites. Hydrodynamics and oceanic influence (in essence dictating sediment type) play a major role in environmental quality. Environmental heterogeneity constituted an important confounding factor for biomarker analysis in the clams' digestive glands since the animals appeared to respond to their immediate surroundings' characteristics rather than the geographical area where they were collected from, despite the relative distance to pollution hot spots. Still, oxidative stress biomarkers (lipid peroxidation and catalase activity) could correlate with each other and to both organic and metallic contamination, whereas metallothionein-like protein induction failed to correlate to any class of sediment toxicants (albeit metals being the most representative pollutants) and appeared to be strongly affected (unlike the previous) by clam size and probably other unknown internal and external variables, among which contaminant interactions should play a major role.

Note on the measurement of bulk density and tapped density of powders according to the European Pharmacopeia.

The apparent volume and compressibility index of commonly used excipients were evaluated according to European Pharmacopeia monograph (seventh edition) in order to study the influence of the procedure conditions. The results suggested that the leveling of the powder inside the cylinder ought to be avoided.

Design of experiment (DoE) as a quality by design (QbD) tool to optimise formulations of lipid nanoparticles for nose-to-brain drug delivery.

INTRODUCTION: The nose-to-brain route has been widely investigated to improve drug targeting to the central nervous system (CNS), where lipid nanoparticles (solid lipid nanoparticles - SLN and nanostructured lipid carriers - NLC) seem promising, although they should meet specific criteria of particle size (PS) <200 nm, polydispersity index (PDI) <0.3, zeta potential (ZP) ~|20| mV and encapsulation efficiency (EE) >80%. To optimize SLN and NLC formulations, design of experiment (DoE) has been recommended as a quality by design (QbD) tool. AREAS COVERED: This review presents recently published work on the optimization of SLN and NLC formulations for nose-to-brain drug delivery. The impact of different factors (or independent variables) on responses (or dependent variables) is critically analyzed. EXPERT OPINION: Different DoEs have been used to optimize SLN and NLC formulations for nose-brain drug delivery, and the independent variables lipid and surfactant concentration and sonication time had the greatest impact on the dependent variables PS, EE, and PDI. Exploring different DoE approaches is important to gain a deeper understanding of the factors that affect successful optimization of SLN and NLC and to facilitate future work improving machine learning techniques.

Anterolateral ligament of the knee-Cadaver study in a Caucasian population.

INTRODUCTION: Despite the recognized importance of the anterolateral ligament (ALL) in rotational stability of the knee, some studies still deny its role and even its existence. We studied the prevalence of the ALL in a Caucasian population, as well as its characteristics and anatomical relationships. MATERIALS AND METHODS: The study was performed on 20 knees from 10 embalmed cadavers. A lateral approach, as described by Steven Claes, was used and the relations of the ALL with the lateral epicondyle, lateral inferior genicular artery, lateral meniscus, Gerdy's tubercle and fibular head were recorded. Its length and its width were also measured. RESULTS: The ALL was identified in 16 knees. Its origin was at a distance inferior to 1mm posterior and proximal to the lateral femoral epicondyle and insertion within a mean distance of 2.1±0.6mm from de tibial articular surface, 20.6±1.3mm from the Gerdy's tubercle and 20.3±1.2mm from the fibular head. In all cases ALL presented mutual fibers with the lateral meniscus. The length was 35.8±4.6mm and the width was 4.2±1.3/4.9±1.0/6.5±1.5mm at its proximal, middle and distal third, respectively. No difference was found between gender and the dimensions of the ligament. CONCLUSIONS: The ALL was found in 80% of the knees. Its origin is closely related to the lateral collateral ligament and its insertion is halfway between the fibular head and the Gerdy's tubercle. In all cases, we verified the connection between ALL and the lateral meniscus.

Anterolateral ligament of the knee-Cadaver study in a Caucasian population. / [Artículo traducido] Ligamento anterolateral de la rodilla. Estudio en cadáver en una población caucásica.

INTRODUCTION: Despite the recognized importance of the anterolateral ligament (ALL) in rotational stability of the knee, some studies still deny its role and even its existence. We studied the prevalence of the ALL in a Caucasian population, as well as its characteristics and anatomical relationships. MATERIALS AND METHODS: The study was performed on 20 knees from 10 embalmed cadavers. A lateral approach, as described by Steven Claes, was used and the relations of the ALL with the lateral epicondyle, lateral inferior genicular artery, lateral meniscus, Gerdy's tubercle and fibular head were recorded. Its length and its width were also measured. RESULTS: The ALL was identified in 16 knees. Its origin was at a distance inferior to 1mm posterior and proximal to the lateral femoral epicondyle and insertion within a mean distance of 2.1±0.6mm from the tibial articular surface, 20.6±1.3mm from the Gerdy's tubercle and 20.3±1.2mm from the fibular head. In all cases ALL presented mutual fibers with the lateral meniscus. The length was 35.8±4.6mm and the width was 4.2±1.3/4.9±1.0/6.5±1.5mm at its proximal, middle and distal third, respectively. No difference was found between gender and the dimensions of the ligament. CONCLUSIONS: The ALL was found in 80% of the knees. Its origin is closely related to the lateral collateral ligament and its insertion is halfway between the fibular head and the Gerdy's tubercle. In all cases, we verified the connection between ALL and the lateral meniscus.

Research-based flow cytometry assays for pathogenic assessment in the human B-cell biology of gene variants revealed in the diagnosis of inborn errors of immunity: a Bruton's tyrosine kinase case-study.

Introduction: Inborn errors of immunity (IEI) are an expanding group of rare diseases whose field has been boosted by next-generation sequencing (NGS), revealing several new entities, accelerating routine diagnoses, expanding the number of atypical presentations and generating uncertainties regarding the pathogenic relevance of several novel variants. Methods: Research laboratories that diagnose and provide support for IEI require accurate, reproducible and sustainable phenotypic, cellular and molecular functional assays to explore the pathogenic consequences of human leukocyte gene variants and contribute to their assessment. We have implemented a set of advanced flow cytometry-based assays to better dissect human B-cell biology in a translational research laboratory. We illustrate the utility of these techniques for the in-depth characterization of a novel (c.1685G>A, p.R562Q) de novo gene variant predicted as probably pathogenic but with no previous insights into the protein and cellular effects, located in the tyrosine kinase domain of the Bruton's tyrosine kinase (BTK) gene, in an apparently healthy 14-year-old male patient referred to our clinic for an incidental finding of low immunoglobulin (Ig) M levels with no history of recurrent infections. Results and discussion: A phenotypic analysis of bone marrow (BM) revealed a slightly high percentage of pre-B-I subset in BM, with no blockage at this stage, as typically observed in classical X-linked agammaglobulinemia (XLA) patients. The phenotypic analysis in peripheral blood also revealed reduced absolute numbers of B cells, all pre-germinal center maturation stages, together with reduced but detectable numbers of different memory and plasma cell isotypes. The R562Q variant allows Btk expression and normal activation of anti-IgM-induced phosphorylation of Y551 but diminished autophosphorylation at Y223 after anti IgM and CXCL12 stimulation. Lastly, we explored the potential impact of the variant protein for downstream Btk signaling in B cells. Within the canonical nuclear factor kappa B (NF-κB) activation pathway, normal IκBα degradation occurs after CD40L stimulation in patient and control cells. In contrast, disturbed IκBα degradation and reduced calcium ion (Ca2+) influx occurs on anti-IgM stimulation in the patient's B cells, suggesting an enzymatic impairment of the mutated tyrosine kinase domain.

Thermosensitive in situ hydrogels of rivastigmine-loaded lipid-based nanosystems for nose-to-brain delivery: characterisation, biocompatibility, and drug deposition studies.

Acetylcholinesterase inhibitors are the most used drugs to manage Alzheimer's disease, although they show low bioavailability in the brain. In this sense, nasal administration has been considered as a promising route for the direct delivery of these drugs to the brain (nose-to-brain delivery). In this work, in situ thermosensitive nasal gels with nanostructured lipid carriers (NLC) and nanoemulsion loaded with an acetylcholinesterase inhibitor (rivastigmine- RVG) were tested. In situ gels containing optimised rivastigmine -loaded NLC and rivastigmine -loaded nanoemulsion were first characterised (size, polydispersity index - PDI, zeta potential - ZP, encapsulation efficiency - EE, loading capacity - LC, pH, osmolarity, organoleptic and morphological analysis and accelerated stability). Afterwards, rheology and texture tests and in vitro studies were conducted to evaluate mucoadhesion, drug release, biocompatibility (with nasal and pulmonary cells, respectively RPMI-2650 and Calu-3) and drug deposition in a nasal cast model. The in situ gels of rivastigmine-loaded NLC and rivastigmine-loaded nanoemulsion had a respective particle/droplet size, PDI, ZP, EE, LC, pH and osmolarity of: 114.00 ± 1.91 nm and 135.80 ± 0.50 nm; 0.45 ± 0.00 and 0.43 ± 0.02; -3.58 ± 1.62 mV and -4.06 ± 1.03 mV; 95.13 ± 0.34% and 89.86 ± 0.19%; 9.30 ± 0.03% and 8.70 ± 0.01%; 6.47 ± 0.01 and 6.451 ± 0.00; 275 ± 0.02 and 280 ± 0.00 mOsm/kg. Organoleptic analysis showed homogeneous appearance, while morphological studies demonstrated that rivastigmine -loaded NLC and rivastigmine -loaded nanoemulsion had a spherical shape. Accelerated stability studies predicted good long-term stability. Rheological and texture analysis revealed that both in situ gels showed desirable characteristics for nasal administration. In addition, suitable nasal mucoadhesion and prolonged drug release were observed. Biocompatibility studies showed low and concentration-dependent cytotoxicity in RPMI 2650 and Calu-3 cells. Nasal deposition studies revealed that 4.0% of the drug was deposited in the olfactory region for both rivastigmine -loaded NLC and rivastigmine -loaded nanoemulsion alone, while in situ gels with these lipid-based nanosystems showed 8.0% of drug deposition. The results of this study highlight the potential of using thermosensitive in situ hydrogels containing lipid-based nanosystems to improve the nose-to-brain delivery of rivastigmine, providing a promising alternative therapeutic option to advance the management of Alzheimer's disease.

Lipid nanoparticles strategies to modify pharmacokinetics of central nervous system targeting drugs: Crossing or circumventing the blood-brain barrier (BBB) to manage neurological disorders.

The main limitation to the success of central nervous system (CNS) therapies lies in the difficulty for drugs to cross the blood-brain barrier (BBB) and reach the brain. Regarding its structure and enzymatic complexity, crossing the BBB is a challenge, although several alternatives have been identified. For instance, the use of drugs encapsulated in lipid nanoparticles has been described as one of the most efficient approaches to bypass the BBB, as they allow the passage of drugs through this barrier, improving brain bioavailability. In particular, solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC) have been a focus of research related to drug delivery to the brain. These systems provide protection of lipophilic drugs, improved delivery and bioavailability, having a major impact on treatments outcomes. In addition, the use of lipid nanoparticles administered via routes that transport drugs directly into the brain seems a promising solution to avoid the difficulties in crossing the BBB. For instance, the nose-to-brain route has gained considerable interest, as it has shown efficacy in 3D human nasal models and in animal models. This review addresses the state of the art on the use of lipid nanoparticles to modify the pharmacokinetics of drugs employed in the management of neurological disorders. A description of the structural components of the BBB, the role of the neurovascular unit and limitations for drugs to entry into the CNS is first addressed, along with the developments to increase drug delivery to the brain, with a special focus on lipid nanoparticles. In addition, the obstacle of BBB complexity in the creation of new effective drugs for the treatment of the most prevalent neurological disorders is also addressed. Finally, the proposed strategies for lipid nanoparticles to reach the CNS, crossing or circumventing the BBB, are described. Although promising results have been reported, especially with the nose-to-brain route, they are still ongoing to assess its real efficacy in vivo in the management of neurological disorders.

Validation of an algorithm to identify incident interstitial lung disease in patients with rheumatoid arthritis.

BACKGROUND/PURPOSE: Interstitial lung disease (ILD) is an important problem for patients with rheumatoid arthritis (RA). However, current approaches to ILD case finding in real-world data have been evaluated only in limited settings and identify only prevalent ILD and not new-onset disease. Our objective was to develop, refine, and validate a claims-based algorithm to identify both prevalent and incident ILD in RA patients compared to the gold standard of medical record review. METHODS: We used administrative claims data 2006-2015 from Medicare to derive a cohort of RA patients. We then identified suspected ILD using variations of ILD algorithms to classify both prevalent and incident ILD based on features of the data that included hospitalization vs. outpatient setting, physician specialty, pulmonary-related diagnosis codes, and exclusions for potentially mimicking pulmonary conditions. Positive predictive values (PPV) of several ILD algorithm variants for both prevalent and incident ILD were evaluated. RESULTS: We identified 234 linkable RA patients with sufficient data to evaluate for ILD. Overall, 108 (46.2%) of suspected cases were confirmed as ILD. Most cases (64%) were diagnosed in the outpatient setting. The best performing algorithm for prevalent ILD had a PPV of 77% (95% CI 67-84%) and for incident ILD was 96% (95% CI 85-100%). CONCLUSION: Case finding in administrative data for both prevalent and incident interstitial lung disease in RA patients is feasible and has reasonable accuracy to support population-based research and real-world evidence generation.

A new DOSXYZnrc method for Monte Carlo simulations of 4D dose distributions.

The purpose of this study is to present a novel method for generating Monte Carlo 4D dose distributions in a single DOSXYZnrc simulation. During a standard simulation, individual energy deposition events are summed up to generate a 3D dose distribution and their associated temporal information is discarded. This means that in order to determine dose distributions as a function of time, separate simulations would have to be run for each interval of interest. Consequently, it has not been clinically feasible until now to routinely perform Monte Carlo simulations of dose rate, time-resolved dose accumulation, or electronic portal imaging devices (EPID) cine-mode images for volumetric modulated arc therapy (VMAT) plans. To overcome this limitation, we modified DOSXYZnrc and defined new input and output variables that allow a time-like parameter associated with each particle history to be binned in a user-defined manner. Under the new code version, computation times are the same as for a standard simulation, and the time-integrated 4D dose is identical to the standard 3D dose. We present a comparison of scintillator measurements and Monte Carlo simulations for dose rate during a VMAT beam delivery, a study of dose rate in a VMAT total body irradiation plan, and simulations of transit (through-patient) EPID cine-mode images.