Decoding clinical and molecular pathways of liver dysfunction in Psoriatic Arthritis: Impact of cumulative methotrexate doses.

BACKGROUND: The occurrence of liver abnormalities in Psoriatic Arthritis (PsA) has gained significant recognition. Identifying key factors at the clinical and molecular level can help to detect high-risk patients for non-alcoholic fatty liver disease in PsA. OBJECTIVES: to investigate the influence of PsA and cumulative doses of methotrexate on liver function through comprehensive in vivo and in vitro investigations. METHODS: A cross-sectional study involving 387 subjects was conducted, 200 patients with PsA, 87 NAFLD-non-PsA patients, and 100 healthy donors (HDs), age and sex-matched. Additionally, a retrospective longitudinal study was carried out, including 83 PsA patients since initiation with methotrexate. Detailed clinical, and laboratory parameters along with liver disease risk were analyzed. In vitro, experiments with hepatocyte cell line (HEPG2) were conducted. RESULTS: PsA patients present increased liver disease risk associated with the presence of cardiometabolic comorbidities, inflammatory markers, onychopathy, and psoriasis. The treatment with PsA serum on hepatocytes encompassed inflammatory, fibrotic, cell stress, and apoptotic processes. At the molecular level, methotrexate impacts liver biology, although the cumulative doses did not affect those alterations, causing any potential damage to liver function at the clinical level. Finally, anti-PDE-4 or anti-JAK decreased the inflammatory profile induced by PsA serum on hepatocytes. CONCLUSION: 1)This study identifies the complex link between liver disease risk, comorbidities, and disease-specific features in PsA patients. 2)Methotrexate dose in PsA patients had no significant effect on liver parameters, confirmed by hepatocyte in vitro studies. 3)Anti-PDE-4 and anti-JAK therapies show promise in reducing PsA serum-induced hepatocyte activation, potentially aiding liver complication management.

Non-late-onset neutropaenia following treatment of multiple sclerosis with ocrelizumab.

Late-onset neutropaenia is defined as an absolute neutrophil count of <1.5×103cells/µL starting>4 weeks after the last dose of rituximab, in the absence of other identifiable causes. Late-onset neutropaenia is a rare adverse reaction to rituximab (observed in approximately 5% of patients). Rheumatic diseases constitute the main indication for rituximab; in these patients, neutropaenia appears after a mean of>28 days. Ocrelizumab is another monoclonal antibody that binds to CD20 (a glycosylated phosphoprotein mainly expressed on the membranes of B-lymphocytes); in January 2018, it was approved for the treatment of relapsing-remitting and primary progressive multiple sclerosis. We present a case of neutropaenia following intravenous infusion of ocrelizumab in a patient with primary progressive multiple sclerosis who presented with neutropaenic fever, herpetic stomatitis, and ecthyma gangrenosum only 20 days after infusion.

Non-late-onset neutropaenia following treatment of multiple sclerosis with ocrelizumab / Neutropenia de aparición no tardía tras el tratamiento con ocrelizumab para la esclerosis múltiple

Late-onset neutropaenia is defined as an absolute neutrophil count of <1.5 × 103 cells/μL starting > 4 weeks after the last dose of rituximab, in the absence of other identifiable causes.Late-onset neutropaenia is a rare adverse reaction to rituximab (observed in approximately 5% of patients). Rheumatic diseases constitute the main indication for rituximab; in these patients, neutropaenia appears after a mean of > 28 days.Ocrelizumab is another monoclonal antibody that binds to CD20 (a glycosylated phosphoprotein mainly expressed on the membranes of B-lymphocytes); in January 2018, it was approved for the treatment of relapsing-remitting and primary progressive multiple sclerosis.We present a case of neutropaenia following intravenous infusion of ocrelizumab in a patient with primary progressive multiple sclerosis who presented with neutropaenic fever, herpetic stomatitis, and ecthyma gangrenosum only 20 days after infusion.(AU)

La neutropenia de aparición tardía se define como un recuento absoluto de neutrófilos < 1,5 × 103/μl que se produce > 4 semanas después de la última dosis de rituximab, precedido por un recuento de neutrófilos normal y sin otra causa identificable. Es una complicación rara del tratamiento con rituximab, habiéndose observado en aproximadamente el 5% de los pacientes tratados, siendo las enfermedades reumáticas su principal indicación, con un tiempo medio hasta el desarrollo de la neutropenia de al menos 28 días. El ocrelizumab, al igual que el rituximab, es un anticuerpo monoclonal dirigido a CD20, una fosfoproteína glicosilada de membrana que se encuentra predominantemente en los linfocitos B y que se aprobó en enero de 2018 para el tratamiento de la esclerosis múltiple remitente recurrente y la esclerosis múltiple progresiva primaria. Se describe un caso de neutropenia después de la infusión de ocrelizumab en un paciente con esclerosis múltiple progresiva primaria que presentó neutropenia febril, estomatitis herpética y ectima gangrenoso solo 20 días después de la infusión.(AU)

Parametrically driving a quantum oscillator into exceptionality.

The mathematical objects employed in physical theories do not always behave well. Einstein's theory of space and time allows for spacetime singularities and Van Hove singularities arise in condensed matter physics, while intensity, phase and polarization singularities pervade wave physics. Within dissipative systems governed by matrices, singularities occur at the exceptional points in parameter space whereby some eigenvalues and eigenvectors coalesce simultaneously. However, the nature of exceptional points arising in quantum systems described within an open quantum systems approach has been much less studied. Here we consider a quantum oscillator driven parametrically and subject to loss. This squeezed system exhibits an exceptional point in the dynamical equations describing its first and second moments, which acts as a borderland between two phases with distinctive physical consequences. In particular, we discuss how the populations, correlations, squeezed quadratures and optical spectra crucially depend on being above or below the exceptional point. We also remark upon the presence of a dissipative phase transition at a critical point, which is associated with the closing of the Liouvillian gap. Our results invite the experimental probing of quantum resonators under two-photon driving, and perhaps a reappraisal of exceptional and critical points within dissipative quantum systems more generally.

Enhancing nonclassical properties of quantum states of light using linear optics.

In this Letter, we present a simple and versatile scheme for enhancing the nonclassical properties of light states using only linear optics and photodetectors. By combining a coherent state |α〉 and an arbitrary pure state of light |ϕ〉 (excluding coherent states) at two beam splitters, we show that the amplitude α of the coherent state can be tuned to filter out specific Fock components and generate states of light with increased nonclassical features. We provide two examples of input states and demonstrate the effectiveness of our scheme in enhancing the sub-Poissonian statistics or the quadrature squeezing of the output states.

A comparative study of the inter-observer variability on Gleason grading against Deep Learning-based approaches for prostate cancer.

BACKGROUND: Among all the cancers known today, prostate cancer is one of the most commonly diagnosed in men. With modern advances in medicine, its mortality has been considerably reduced. However, it is still a leading type of cancer in terms of deaths. The diagnosis of prostate cancer is mainly conducted by biopsy test. From this test, Whole Slide Images are obtained, from which pathologists diagnose the cancer according to the Gleason scale. Within this scale from 1 to 5, grade 3 and above is considered malignant tissue. Several studies have shown an inter-observer discrepancy between pathologists in assigning the value of the Gleason scale. Due to the recent advances in artificial intelligence, its application to the computational pathology field with the aim of supporting and providing a second opinion to the professional is of great interest. METHOD: In this work, the inter-observer variability of a local dataset of 80 whole-slide images annotated by a team of 5 pathologists from the same group was analyzed at both area and label level. Four approaches were followed to train six different Convolutional Neural Network architectures, which were evaluated on the same dataset on which the inter-observer variability was analyzed. RESULTS: An inter-observer variability of 0.6946 κ was obtained, with 46% discrepancy in terms of area size of the annotations performed by the pathologists. The best trained models achieved 0.826±0.014κ on the test set when trained with data from the same source. CONCLUSIONS: The obtained results show that deep learning-based automatic diagnosis systems could help reduce the widely-known inter-observer variability that is present among pathologists and support them in their decision, serving as a second opinion or as a triage tool for medical centers.

Wide & Deep neural network model for patch aggregation in CNN-based prostate cancer detection systems.

Prostate cancer (PCa) is one of the most commonly diagnosed cancer and one of the leading causes of death among men, with almost 1.41 million new cases and around 375,000 deaths in 2020. Artificial Intelligence algorithms have had a huge impact on medical image analysis, including digital histopathology, where Convolutional Neural Networks (CNNs) are used to provide a fast and accurate diagnosis, supporting experts in this task. To perform an automatic diagnosis, prostate tissue samples are first digitized into gigapixel-resolution whole-slide images. Due to the size of these images, neural networks cannot use them as input and, therefore, small subimages called patches are extracted and predicted, obtaining a patch-level classification. In this work, a novel patch aggregation method based on a custom Wide & Deep neural network model is presented, which performs a slide-level classification using the patch-level classes obtained from a CNN. The malignant tissue ratio, a 10-bin malignant probability histogram, the least squares regression line of the histogram, and the number of malignant connected components are used by the proposed model to perform the classification. An accuracy of 94.24% and a sensitivity of 98.87% were achieved, proving that the proposed system could aid pathologists by speeding up the screening process and, thus, contribute to the fight against PCa.

Non-late-onset neutropaenia following treatment of multiple sclerosis with ocrelizumab.

Late-onset neutropaenia is defined as an absolute neutrophil count of <1.5×103cells/µL starting>4 weeks after the last dose of rituximab, in the absence of other identifiable causes. Late-onset neutropaenia is a rare adverse reaction to rituximab (observed in approximately 5% of patients). Rheumatic diseases constitute the main indication for rituximab; in these patients, neutropaenia appears after a mean of>28 days. Ocrelizumab is another monoclonal antibody that binds to CD20 (a glycosylated phosphoprotein mainly expressed on the membranes of B-lymphocytes); in January 2018, it was approved for the treatment of relapsing-remitting and primary progressive multiple sclerosis. We present a case of neutropaenia following intravenous infusion of ocrelizumab in a patient with primary progressive multiple sclerosis who presented with neutropaenic fever, herpetic stomatitis, and ecthyma gangrenosum only 20 days after infusion.

Polytetrafluoroethylene versus polypropylene mesh during laparoscopic totally extraperitoneal (TEP) repair of inguinal hernia: short- and long-term results of a double-blind clinical randomized controlled trial.

PURPOSE: Aim of the study is to compare macroporous (> 1 mm2) polytetrafluoroethylene mesh (LP-PTFE) versus microporous (< 1 mm2) polypropylene mesh (SP-PPL) in terms of postoperative acute and chronic discomfort and pain, difficulty in mesh handling and long-term recurrence rate. METHODS: Fifty-two patients with bilateral hernia were enrolled in this double-blind randomized controlled trial (NCT02023203). Each hernia, in the same patient, was randomized to implant LP-PTFE or SP-PPL mesh during totally extraperitoneal laparoscopic hernia repair. Patients were followed at 7 days, 1, 3, 6, 12 and 60 months after surgery. Visual analog scale (VAS) score was employed to evaluate the outcomes. Student's t test was used in case of normally distributed continuous variables, while the nonparametric Mann-Whitney U test was used in case of not normally distributed variables. Chi square test was used for analysis of categorical variables. RESULTS: Median VAS discomfort score with SP-PPL was significantly higher than LP-PTFE at 1 and 3 months after surgery (p = 0.003 in both cases). LP-PTFE showed significantly lower median score than SP-PPL at 7 days after surgery (p = 0.025) regarding pain at movement. Testicular pain was lower in case of LP-PTFE than SP-PPL at 7 days, 1 and 3 months after surgery (p = 0.005, p = 0.004 and p = 0.004, respectively). LP-PTFE was significantly more difficult to handle (p = 0.001). At 60 months, one recurrence was observed in the LP-PTFE group (p = 1.0000). CONCLUSIONS: LP-PTFE has less postoperative discomfort and pain up to 3 months after surgery, without differences after that period, although it shows more difficulty in handling and recurrences occur even if not statistically significant.

Symmetry-mode analysis for intuitive observation of structure-property relationships in the lead-free antiferroelectric (1-x)AgNbO3-xLiTaO3.

Functional materials are of critical importance to electronic and smart devices. A deep understanding of the structure-property relationship is essential for designing new materials. In this work, instead of utilizing conventional atomic coordinates, a symmetry-mode approach is successfully used to conduct structure refinement of the neutron powder diffraction data of (1-x)AgNbO3-xLiTaO3 (0 ≤ x ≤ 0.09) ceramics. This provides rich structural information that not only clarifies the controversial symmetry assigned to pure AgNbO3 but also explains well the detailed structural evolution of (1-x)AgNbO3-xLiTaO3 (0 ≤ x ≤ 0.09) ceramics, and builds a comprehensive and straightforward relationship between structural distortion and electrical properties. It is concluded that there are four relatively large-amplitude major modes that dominate the distorted Pmc21 structure of pure AgNbO3, namely a Λ3 antiferroelectric mode, a T4+ a - a - c 0 octahedral tilting mode, an H2 a 0 a 0 c +/a 0 a 0 c - octahedral tilting mode and a Γ4- ferroelectric mode. The H2 and Λ3 modes become progressively inactive with increasing x and their destabilization is the driving force behind the composition-driven phase transition between the Pmc21 and R3c phases. This structural variation is consistent with the trend observed in the measured temperature-dependent dielectric properties and polarization-electric field (P-E) hysteresis loops. The mode crystallography applied in this study provides a strategy for optimizing related properties by tuning the amplitudes of the corresponding modes in these novel AgNbO3-based (anti)ferroelectric materials.

Bifidobacterium breve IPLA20005 affects in vitro the expression of hly and luxS genes, related to the virulence of Listeria monocytogenes Lm23.

Mechanistic features that characterize the interaction and inhibition of the food-borne pathogen Listeria monocytogenes by members of the genus Bifidobacterium still remain unclear. In the present work, we tried to shed light on the influence that co-cultivation of L. monocytogenes with Bifidobacterium breve may exert on both microorganisms and on virulence of the pathogen. Production of acetate and lactate was measured by gas chromatography and high-performance liquid chromatography, respectively; bacterial counts were obtained by plate count; gene expression was determined by RT-qPCR; and haemolytic activity was analyzed against goat erythrocytes. We found slightly but significantly lower final counts of Listeria and Bifidobacterium (p < 0.05) and lower haemolytic efficiency in L. monocytogenes cells from cocultures than in those from monocultures. In contrast, the hly and luxS genes, which code for the cytolysin listeriolysin O and participate in biofilm formation, respectively, were overexpressed when L. monocytogenes was grown in coculture. This indicates that the presence of Bifidobacterium is able to modify the gene expression and haemolytic activity of L. monocytogenes when both microorganisms grow together.

Silver and gold nanoparticles in nanometric confined templates: synthesis and alloying within the anisotropic pores of oblique angle deposited films.

In this work we have developed an infiltration methodology to incorporate metal nanoparticles (NPs) of controlled size and shape into the open voids available in oblique angle deposited thin films. These NPs exhibited well-defined surface plasmon resonances (SPRs). The nanometric confined space provided by their porous microstructure has been used as a template for the growth of anisotropic NPs with interesting SPR properties. The fabrication methodology has been applied for the preparation of films with embedded Ag and Au NPs with two associated plasmon resonance features that developed a dichroic behaviour when examined with linearly polarized light. A confined alloying process was induced by near IR nanosecond laser irradiation yielding bimetallic NPs with SPR features covering a large zone of the electromagnetic spectrum. The possibilities of the method for the tailored fabrication of a wide range colour palette based on SPR features are highlighted.

The interaction between hybrid organic-inorganic halide perovskite and selective contacts in perovskite solar cells: an infrared spectroscopy study.

The interaction of hybrid organic-inorganic halide perovskite and selective contacts is crucial to get efficient, stable and hysteresis-free perovskite-based solar cells. In this report, we analyze the vibrational properties of methylammonium lead halide perovskites deposited on different substrates by infrared absorption (IR) measurements (4000-500 cm(-1)). The materials employed as substrates are not only characterized by different chemical natures (TiO2, ZnO and Al2O3), but also by different morphologies. For all of them, we have investigated the influence of these substrate properties on perovskite formation and its degradation by humidity. The effect of selective-hole contact (Spiro-OmeTad and P3HT) layers on the degradation rate by moisture has also been studied. Our IR results reveal the existence of a strong interaction between perovskite and all ZnO materials considered, evidenced by a shift of the peaks related to the N-H vibrational modes. The interaction even induces a morphological change in ZnO nanoparticles after perovskite deposition, pointing to an acid-base reaction that takes place through the NH3(+) groups of the methylammonium cation. Our IR and X-ray diffraction results also indicate that this specific interaction favors perovskite decomposition and PbI2 formation for ZnO/perovskite films subjected to humid conditions. Although no interaction is observed for TiO2, Al2O3, and the hole selective contact, the morphology and chemical nature of both contacts appear to play an important role in the rate of degradation upon exposure to moisture.

Glucolytic fingerprinting reveals metabolic groups within the genus Bifidobacterium: an exploratory study.

Microorganisms of the genus Bifidobacterium are inhabitants of diverse niches including the digestive tract of humans and animals. The species Bifidobacterium adolescentis, Bifidobacterium animalis, Bifidobacterium bifidum, Bifidobacterium breve and Bifidobacterium longum have qualified presumption of safety status granted by EFSA and several strains are considered probiotic, and are being included in functional dairy fermented products. In the present work we carried out a preliminary exploration of general metabolic characteristics and organic acid production profiles of a reduced number of strains selected from these and other species of the genus Bifidobacterium. The use of resting cells allowed obtaining metabolic fingerprints without interference of metabolites accumulated during growth in culture media. Acetic acid was the most abundant organic acid formed per mol of glucose consumed (from 1.07 ± 0.03 to 1.71 ± 0.22 mol) followed by lactic acid (from 0.34 ± 0.06 to 0.90 ± 0.12 mol), with moderate differences in production among strains; pyruvic, succinic and formic acids were also produced at considerably lower proportions, with variability among strains. The acetic to lactic acid ratio showed lower values in stationary phase as regard to the exponential phase for most, but not all, the microorganisms; this was due to a decrease in acetic acid molar proportions together with increases of lactic acid proportions in stationary phase. A linear discriminant analysis allowed to cluster strains into species with 51-100% probability, evidencing different metabolic profiles, according to the relative production of organic acids from glucose by resting cells, of microorganisms collected at the exponential phase of growth. Looking for a single metabolic marker that could adequately discriminate metabolic groups, we found that groups established by the acetic to lactic acid ratio fit well with differences previously evidenced by the discriminant analysis. The proper establishment of metabolic groups within the genus Bifidobacterium could help to select the best suited probiotic strains for specific applications.

Analysis of 17 neurotransmitters, metabolites and precursors in zebrafish through the life cycle using ultrahigh performance liquid chromatography-tandem mass spectrometry.

An ultrahigh performance liquid chromatography-tandem mass spectrometry method for the identification and quantification of neurotransmitters, metabolites and precursors at different stages in zebrafish life was developed. Betaine, glutamine, glutamic acid, γ-aminobutyric acid, phosphocholine, glycerophosphocholine, cytidine 5'-diphosphocholine, choline, acetylcholine, dopamine, norepinephrine, serotonin, tyrosine, epinephrine, tryptophan, 5-hydroxyindolacetic acid and agmatine were selected as analytes. The method consisted of a simple deproteinization of samples using methanol and formic acid, subsequent injection onto the chromatographic equipment and quantification with a triple quadrupole mass spectrometer detector using an electrospray ionization interface in positive mode. Limits of detection ranged from 0.02 to 11ngmL(-1) and limits of quantification from 0.1 to 38ngmL(-1), depending on the analyte. The method was validated according to US Food and Drugs Administration (FDA) guideline for bioanalytical assays. Precision, expressed as relative standard deviation (%RSD), was lower than 15% in all cases, and the determination coefficient (R(2)) was equal or higher than 99.0% with a residual deviation for each calibration point lower than ±25%. Mean recoveries were between 85% and 115%. The method was applied to determine of these compounds in zebrafish from early stages of development to adulthood and showed the time-course of neurotransmitters and others neurocompounds through the life cycle. The possibility of measuring up to 17 compounds related with the main neurotransmitter systems in a simple analytical method will complement and reinforce the use of zebrafish in multiple applications in the field of neurosciences. The proposed method will facilitate future studies related with brain development.

Quantitative determination of ß-hydroxymethylbutyrate and leucine in culture media and microdialysates from rat brain by UHPLC-tandem mass spectrometry.

The main objective of the present work was to develop a method to determine ß-hydroxymethylbutyrate (HMB) and leucine (Leu) in culture media and brain microdialysates. An accurate, selective, and cost-effective method, based on the use of ultrahigh-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS), was developed for the identification and quantification of both compounds. The method consisted of sample dilution, direct injection onto the chromatographic equipment, and quantification with a triple quadrupole mass spectrometer using an electrospray ionization interface in positive mode. The procedure and the UHPLC-MS/MS parameters were accurately optimized to achieve the highest recoveries and to enhance the analytical characteristics of the method. For chromatographic separation, an Acquity UPLC BEH Hilic column using acetonitrile-water gradient with formic acid as additive was employed. The total run time was 4 min. The limits of detection (LODs) obtained ranged from 0.01 to 0.04 µg mL(-1), and the limits of quantification (LOQs) ranged from 0.04 to 0.12 µg mL(-1). Precision (expressed as relative standard deviation) was lower than 15 %, and the determination coefficient (R (2)) was higher than 99.0 % with a residual deviation for each calibration point lower than ±25 %. Mean recoveries were between 85 and 115 %. The method was successfully applied to the analysis of both compounds, HMB and Leu, in samples obtained from an experiment of blood-brain barrier (BBB) passage in vitro and to an experiment of brain microdialysis in rats in vivo after an oral challenge with HMB to detect its appearance in the brain.

Quantitative determination of neurotransmitters, metabolites and derivates in microdialysates by UHPLC-tandem mass spectrometry.

The main objective of the present work is to study the time-course of rat brain neurotransmitters in vivo after an oral challenge with a nutritional ingredient or an external stimulus, such as a chemical agent. An ultrahigh performance liquid chromatography-tandem mass spectrometry method for the identification and quantification of neurotransmitters, metabolites and derivates in microdialysates from rat brain was previously developed. Betaine, glutamine, glutamic acid, gamma-aminobutyric acid, phosphocholine, glycerophosphocholine, cytidine 5'-diphosphocholine, choline, acetylcholine, dopamine, norepinephrine, serotonin, tyrosine, epinephrine, tryptophan and 5-hydroxyindoleacetic acid were selected as analytes. The method involves direct injection of samples of microdialysates from rat brain onto the chromatographic equipment and quantification with a triple quadrupole mass spectrometer detector using an electrospray ionization interface in positive mode. The limits of detection ranged from 0.1 to 50 ng mL(-1) and the limits of quantification from 0.3 to 200 ng mL(-1). The inter- and intra-day variability were lower than 15%. Recovery rates ranged from 85% to 115%.