Glycogen Synthase Kinase-3ß Inhibitor VP3.15 Ameliorates Neurogenesis, Neuronal Loss and Cognitive Impairment in a Model of Germinal Matrix-intraventricular Hemorrhage of the Preterm Newborn.

Advances in neonatology have significantly reduced mortality rates due to prematurity. However, complications of prematurity have barely changed in recent decades. Germinal matrix-intraventricular hemorrhage (GM-IVH) is one of the most severe complications of prematurity, and these children are prone to suffer short- and long-term sequelae, including cerebral palsy, cognitive and motor impairments, or neuropsychiatric disorders. Nevertheless, GM-IVH has no successful treatment. VP3.15 is a small, heterocyclic molecule of the 5-imino-1,2,4-thiadiazole family with a dual action as a phosphodiesterase 7 and glycogen synthase kinase-3ß (GSK-3ß) inhibitor. VP3.15 reduces neuroinflammation and neuronal loss in other neurodegenerative disorders and might ameliorate complications associated with GM-IVH. We administered VP3.15 to a mouse model of GM-IVH. VP3.15 reduces the presence of hemorrhages and microglia in the short (P14) and long (P110) term. It ameliorates brain atrophy and ventricle enlargement while limiting tau hyperphosphorylation and neuronal and myelin basic protein loss. VP3.15 also improves proliferation and neurogenesis as well as cognition after the insult. Interestingly, plasma gelsolin levels, a feasible biomarker of brain damage, improved after VP3.15 treatment. Altogether, our data support the beneficial effects of VP3.15 in GM-IVH by ameliorating brain neuroinflammatory, vascular and white matter damage, ultimately improving cognitive impairment associated with GM-IVH.

Predicting Risk of Severe Toxicity and Early Death in Older Adult Patients Treated with Chemotherapy.

BACKGROUND: Determining the risk of grade 3-5 toxicity and early death (ED) is important to plan chemotherapy in older adult patients with cancer. Our objective was to identify factors predicting these complications at the time of treatment initiation. METHODS: 234 patients aged ≥70 were subjected to a geriatric assessment and variables related to the tumor and the treatment were also collected. Logistic regression multivariable analysis was used to relate these factors with the appearance of grade 3-5 toxicity and ED. Predictive scores for both toxicity and ED were then developed. RESULTS: Factors related to grade 3-5 toxicity were hemoglobin, MAX2 index, ADL, and the CONUT score. Factors related to ED were tumor stage and the GNRI score. Two predictive scores were developed using these variables. ROC curves for the prediction of toxicity and ED were 0.71 (95% CI: 0.64-0.78) and 0.73 (95% CI: 0.68-0.79), respectively. CONCLUSIONS: Two simple and reliable scores were developed to predict grade 3-5 toxicity and ED in older adult patients with cancer. This may be helpful in treatment planning.

Steering self-organisation through confinement.

Self-organisation is the spontaneous emergence of spatio-temporal structures and patterns from the interaction of smaller individual units. Examples are found across many scales in very different systems and scientific disciplines, from physics, materials science and robotics to biology, geophysics and astronomy. Recent research has highlighted how self-organisation can be both mediated and controlled by confinement. Confinement is an action over a system that limits its units' translational and rotational degrees of freedom, thus also influencing the system's phase space probability density; it can function as either a catalyst or inhibitor of self-organisation. Confinement can then become a means to actively steer the emergence or suppression of collective phenomena in space and time. Here, to provide a common framework and perspective for future research, we examine the role of confinement in the self-organisation of soft-matter systems and identify overarching scientific challenges that need to be addressed to harness its full scientific and technological potential in soft matter and related fields. By drawing analogies with other disciplines, this framework will accelerate a common deeper understanding of self-organisation and trigger the development of innovative strategies to steer it using confinement, with impact on, e.g., the design of smarter materials, tissue engineering for biomedicine and in guiding active matter.

Correction: Evaporation-driven liquid flow in sessile droplets.

Correction for 'Evaporation-driven liquid flow in sessile droplets' by Hanneke Gelderblom et al., Soft Matter, 2022, 18, 8535-8553, https://doi.org/10.1039/D2SM00931E.

Proteomics Characterization of Clear Cell Renal Cell Carcinoma.

PURPOSE: To explore the tumor proteome of patients diagnosed with localized clear cell renal cancer (ccRCC) and treated with surgery. MATERIAL AND METHODS: A total of 165 FFPE tumor samples from patients diagnosed with ccRCC were analyzed using DIA-proteomics. Proteomics ccRCC subtypes were defined using a consensus cluster algorithm (CCA) and characterized by a functional approach using probabilistic graphical models and survival analyses. RESULTS: We identified and quantified 3091 proteins, including 2026 high-confidence proteins. Two proteomics subtypes of ccRCC (CC1 and CC2) were identified by CC using the high-confidence proteins only. Characterization of molecular differences between CC1 and CC2 was performed in two steps. First, we defined 514 proteins showing differential expression between the two subtypes using a significance analysis of microarrays analysis. Proteins overexpressed in CC1 were mainly related to translation and ribosome, while proteins overexpressed in CC2 were mainly related to focal adhesion and membrane. Second, a functional analysis using probabilistic graphical models was performed. CC1 subtype is characterized by an increased expression of proteins related to glycolysis, mitochondria, translation, adhesion proteins related to cytoskeleton and actin, nucleosome, and spliceosome, while CC2 subtype showed higher expression of proteins involved in focal adhesion, extracellular matrix, and collagen organization. CONCLUSIONS: ccRCC tumors can be classified in two different proteomics subtypes. CC1 and CC2 present specific proteomics profiles, reflecting alterations of different molecular pathways in each subtype. The knowledge generated in this type of studies could help in the development of new drugs targeting subtype-specific deregulated pathways.

Clogging of noncohesive suspensions through constrictions using an efficient discrete particle solver with unresolved fluid flow.

When objects are forced to flow through constrictions their transport can be frustrated temporarily or permanently due to the formation of arches in the region of the bottleneck. While such systems have been intensively studied in the case of solid particles in a gas phase being forced by gravitational forces, the case of solid particles suspended in a liquid phase, forced by the liquid itself, has received much less attention. In this case, the influence of the liquid flow on the transport efficiency is not well understood yet, leading to several apparently trivial but yet unanswered questions, e.g., would an increase of the liquid flow improve the transport of particles or worsen it? Although some experimental data are already available, they lack enough detail to give a complete answer to such a question. Numerical models would be needed to scrutinize the system deeper. In this paper, we study this system making use of an advanced discrete particle solver (mercurydpm) and an approximated numerical model for the liquid drag and compare the results with experimental data.

Evaporation-driven liquid flow in sessile droplets.

The evaporation of a sessile droplet spontaneously induces an internal capillary liquid flow. The surface-tension driven minimisation of surface area and/or surface-tension differences at the liquid-gas interface caused by evaporation-induced temperature or chemical gradients set the liquid into motion. This flow drags along suspended material and is one of the keys to control the material deposition in the stain that is left behind by a drying droplet. Applications of this principle range from the control of stain formation in the printing and coating industry, to the analysis of DNA, to forensic and medical research on blood stains, and to the use of evaporation-driven self-assembly for nanotechnology. Therefore, the evaporation of sessile droplets attracts an enormous interest from not only the fluid dynamics, but also the soft matter, chemistry, biology, engineering, nanotechnology and mathematics communities. As a consequence of this broad interest, knowledge on evaporation-driven flows in drying droplets has remained scattered among the different fields, leading to various misconceptions and misinterpretations. In this review we aim to unify these views, and reflect on the current understanding of evaporation-driven liquid flows in sessile droplets in the light of the most recent experimental and theoretical advances. In addition, we outline open questions and indicate promising directions for future research.

MiRNAs in renal cell carcinoma

MicroRNAs (miRNAs) are small RNA sequences that act as post-transcriptional regulatory genes to control many cellular processes through pairing bases with a complementary messenger RNA (mRNA). A single miRNA molecule can regulate more than 200 different transcripts and the same mRNA can be regulated by multiple miRNAs. In this review, we highlight the importance of miRNAs and collect the existing evidence on their relationship with kidney cancer. (AU)

Evaporation of a Sessile Colloidal Water-Glycerol Droplet: Marangoni Ring Formation.

The transport and aggregation of particles in suspensions is an important process in many physicochemical and industrial processes. In this work, we study the transport of particles in an evaporating binary droplet. Surprisingly, the accumulation of particles occurs not only at the contact line (due to the coffee-stain effect) or at the solid substrate (due to sedimentation) but also at a particular radial position near the liquid-air interface, forming a "ring", which we term as the Marangoni ring. The formation of this ring is primarily attributed to the solutal Marangoni flow triggered by the evaporation dynamics of the water-glycerol droplet. Experiments and simulations show fair agreement in the volume evolution and the general structure of the solutal Marangoni flow, that is, the Marangoni vortex. Experiments show that the location of the Marangoni ring is strongly correlated with the Marangoni vortex. However, finite element numerical simulations fail to describe the particle distribution seen in the experiments. Interestingly, the particles not only accumulate to form the Marangoni ring but also assemble as colloidal crystals close to the liquid-air interface, yielding iridescence. The formation of the colloidal crystals in the experiments is strong evidence that non-hydrodynamic interactions, which are not represented in the simulations, also play a significant role in our system.

Transcultural Validation of a Spanish Version of the Quality of Life in Epidermolysis Bullosa Questionnaire.

INTRODUCTION: Epidermolysis bullosa (EB) is a relatively infrequent genodermatosis for which there is still no cure, and which impacts the quality of life of those that are affected by it. The Quality of Life evaluation in Epidermolysis Bullosa (QoLEB) questionnaire was specifically developed for English-speaking persons with EB. OBJECTIVES: To undertake the transcultural adaptation and analysis of the psychometric properties of a Spanish version of the QoLEB questionnaire. METHOD: We designed an observational study to implement the process of translation and validation of the scale in accordance with World Health Organisation guidelines. We assessed the content validity of the Spanish version with the participation of 33 adult patients who presented with four principal subtypes of EB. The subjects were examined and evaluated using the QoLEB and Short Form-36 (SF-36) questionnaires. RESULTS: The Spanish version of the QoLEB displayed excellent internal consistency and content validity, α = 0.91. Test-retest reliability was likewise excellent (ps = 0.93), as was the reliability among subtypes (range ps = 0.82-0.93). The functional part of the QoLEB correlated well with the SF-36 physical component summary (ps = 0.70). The emotional QoLEB was moderately correlated with the SF-36 mental component summary (ps = 0.49). Significant discriminant validity existed between the global score of the questionnaire (p = 0.033) and the functional scale (p = 0.003). CONCLUSIONS: The Spanish version of the QoLEB questionnaire can be recommended for use in any subsequent studies seeking to assess the efficacy of possible treatments and care programmes in this group.

MiRNAs in renal cell carcinoma.

MicroRNAs (miRNAs) are small RNA sequences that act as post-transcriptional regulatory genes to control many cellular processes through pairing bases with a complementary messenger RNA (mRNA). A single miRNA molecule can regulate more than 200 different transcripts and the same mRNA can be regulated by multiple miRNAs. In this review, we highlight the importance of miRNAs and collect the existing evidence on their relationship with kidney cancer.

Measures to evaluate quality of care in renal cancer: results of a Delphi study in Spain

PurposeTo review current measures for renal cancer care and develop a comprehensive and updated list of measures for their practical use in Spain.MethodsThe study was developed by Fundación ECO, a Spanish foundation aiming to improve oncology quality of care. A systematic literature review was carried out to identify measures and knowledge gaps. A scientific committee composed of nine experts reviewed the literature findings and added measures. A preliminary list of 42 measures was evaluated with the Delphi method to gather feedback from 47 medical oncology experts in Spain. Experts scored the appropriateness of the measures and ranked their priority in two consecutive online surveys. The scientific committee reviewed the Delphi results and developed the measures. A technical group from Universidad Francisco de Vitoria conducted and oversaw the Delphi method.ResultsThe Delphi method led to consensus on all 42 measures. The scientific committee used a prioritisation matrix to select 25 of these measures for evaluating quality of care in renal cancer. These measures regarded structure, process, and outcome and covered general management, diagnosis, treatment, follow-up, and evaluation of health outcomes. Easy-to-use index cards were developed for all 25 measures, including their definition, formula, acceptable level of attainment, and rationale.ConclusionsThis manuscript aims to provide healthcare professionals with expert- and evidence-based measures that are useful for evaluating quality of care in renal cancer in Spain and cover all aspects and stages.

The effect of neoadjuvant chemotherapy among patients undergoing radical cystectomy for variant histology bladder cancer: A systematic review.

OBJECTIVE: To systematically review the evidence about the effect of neoadjuvant chemotherapy (NAC) for muscle-invasive bladder cancer (MIBC) with pure urothelial carcinoma (pUC) in radical cystectomy (RC) candidates affected by variant histology (VH) bladder cancer. METHODS: A review of the current literature was conducted through the Medline and National Center for Biotechnology Information (NCBI) PubMed, Scopus databases in May 2020. The updated Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were followed for this systematic review. Keywords used were 'bladder cancer', 'bladder carcinoma', 'bladder tumour' and 'bladder cancer variants' and 'neoadjuvant chemotherapy'. Only original articles in English published after 2000 and reporting oncological outcomes a series of more than five patients with VH were included. We excluded series in which the oncological outcomes of patients with pUC and VH were undistinguishable. RESULTS: The literature search identified 2231 articles. A total of 51 full-text articles were assessed for eligibility, with 17 eventually considered for systematic review, for a cohort of 450,367 patients, of which 5010 underwent NAC + RC. The median age at initial diagnosis ranged from 61 to 71 years. Most patients received cisplatin-gemcitabine, methotrexate-vinblastine-adriamycin-cisplatin, or carboplatin-based chemotherapy. Only one study reported results of neoadjuvant immunotherapy. The median follow-up ranged from 1 to 120 months. The results showed that squamous cell carcinoma (SCC) is less sensitive to NAC than pUC and that SCC predicts poorer prognosis. NAC was found to be a valid approach in treating small cell carcinoma and may have potential benefit in micropapillary carcinoma. CONCLUSIONS: NAC showed the best oncological outcomes in small cell variants and micropapillary carcinoma, while NAC survival benefit for SCC and adenocarcinoma variants needs further studies. Drawing definite considerations on the efficacy of NAC in VH is complicated due to the heterogeneity of present literature. Present results need to be confirmed in randomised controlled trials.

Measures to evaluate quality of care in renal cancer: results of a Delphi study in Spain.

PURPOSE: To review current measures for renal cancer care and develop a comprehensive and updated list of measures for their practical use in Spain. METHODS: The study was developed by Fundación ECO, a Spanish foundation aiming to improve oncology quality of care. A systematic literature review was carried out to identify measures and knowledge gaps. A scientific committee composed of nine experts reviewed the literature findings and added measures. A preliminary list of 42 measures was evaluated with the Delphi method to gather feedback from 47 medical oncology experts in Spain. Experts scored the appropriateness of the measures and ranked their priority in two consecutive online surveys. The scientific committee reviewed the Delphi results and developed the measures. A technical group from Universidad Francisco de Vitoria conducted and oversaw the Delphi method. RESULTS: The Delphi method led to consensus on all 42 measures. The scientific committee used a prioritisation matrix to select 25 of these measures for evaluating quality of care in renal cancer. These measures regarded structure, process, and outcome and covered general management, diagnosis, treatment, follow-up, and evaluation of health outcomes. Easy-to-use index cards were developed for all 25 measures, including their definition, formula, acceptable level of attainment, and rationale. CONCLUSIONS: This manuscript aims to provide healthcare professionals with expert- and evidence-based measures that are useful for evaluating quality of care in renal cancer in Spain and cover all aspects and stages.

Catastrophic Phase Inversion in High-Reynolds-Number Turbulent Taylor-Couette Flow.

Emulsions are omnipresent in the food industry, health care, and chemical synthesis. In this Letter the dynamics of metastable oil-water emulsions in highly turbulent (10^{11}≤Ta≤3×10^{13}) Taylor-Couette flow, far from equilibrium, is investigated. By varying the oil-in-water void fraction, catastrophic phase inversion between oil-in-water and water-in-oil emulsions can be triggered, changing the morphology, including droplet sizes, and rheological properties of the mixture, dramatically. The manifestation of these different states is exemplified by combining global torque measurements and local in situ laser induced fluorescence microscopy imaging. Despite the turbulent state of the flow and the dynamic equilibrium of the oil-water mixture, the global torque response of the system is found to be as if the fluid were Newtonian, and the effective viscosity of the mixture was found to be several times bigger or smaller than either of its constituents.

Soft cavitation in colloidal droplets.

When a pure droplet evaporates inside an elastic medium, two instabilities are typically observed. As the droplet shrinks, the elastic medium needs to deform and elastic tension builds up. At a critical strain, accumulated tension at the gel-droplet interface is released by developing creases. The droplet keeps shrinking beyond this point, pulling the elastic network and therefore decreasing the pressure in the liquid phase. This drives the liquid phase into a metastable state, and leads to the second instability: the nucleation of a vapour bubble in the liquid phase by cavitation. These instabilities consistently occur in the described order whenever a pure liquid (water, in this case) is used. The presence of colloidal particles inside droplets is common both in vitro and in natural environments, and they can change such phenomenology significantly by stimulating cavitation events before any creasing instability. In this work, we study the role of colloidal particle size and concentration on the early inception of cavitation in water droplets in an elastic medium. Our results reveal an unexpected dependence with the particle size and with the size distribution of the colloidal particles. Given the simplicity and reliability of the system and preparation, the method described here could be eventually used to measure tensile strengths of particle solutions with accuracy.

Evaporation-driven colloidal cluster assembly using droplets on superhydrophobic fractal-like structures.

Microparticles can be considered building units for functional systems, but their assembly into larger structures typically involves complex methods. In this work, we show that a large variety of macro-agglomerate clusters ("supra-particles") can be obtained, by systematically varying the initial particle concentration in an evaporating droplet, spanning more than 3 decades. The key is the use of robust superhydrophobic substrates: in this study we make use of a recently discovered kind of patterned surface with fractal-like microstructures which dramatically reduce the contact of the droplet with the solid substrate. Our results show a clear transition from quasi-2D to 3D clusters as a function of the initial particle concentration, and a clear transition from unstable to stable 3D spheroids as a function of the evaporation rate. The origin of such shape transitions can respectively be found in the dynamic wetting of the fractal-like structure, but also in the enhanced mechanical stability of the particle agglomerate as its particle packing fraction increases.

Inmunoterapia con ácaros Valergen por vía sublingual y subcutánea en pacientes alérgicos. Cabaiguán 2010-2019 / Sublingual and subcutaneous Valergen mite immunotherapy in allergic patients in Cabaiguán 2010-2019

RESUMEN Fundamento: La inmunoterapia consiste en la administración de dosis crecientes del alérgeno para controlar la sensibilidad hacia este. Objetivo: Describir el comportamiento de la inmunoterapia por vía subcutánea o sublingual a ácaros. Metodología: Estudio retrospectivo realizado en Cabaiguán, periodo de 2010 a 2019, el universo de 267 pacientes con pruebas positivas a ácaros y la muestra de 53 pacientes. Los datos se obtuvieron del registro de datos. Resultados: Usó la vía sublingual el 60.4 %, predominó el grupo de edad entre 5-18 años (41.5 %), la vía subcutánea se utilizó en un 39.6 %, fue más frecuente en el sexo masculino (58.5 %). La vía subcutánea se indicó mayoritariamente en la rinitis alérgica (20.7 %) y la sublingual en el asma (32.1 %); para ambas, fue el Dermatofagoide pteronyssinus el ácaro de mayor sensibilidad y utilización (43.4 %), el tiempo de administración dominante fue de 3 años (67.9 %). El control de los síntomas se alcanzó con la vía sublingual (37.7 %). En la vía sublingual no se presentaron eventos adversos en el 43.3 %, con la vía subcutánea 11.3 % de los eventos adversos fueron locales y 7.6 % sistémicos leves. Conclusiones: La vía sublingual fue la más utilizada, la de mayor control de los síntomas y menos eventos adversos en el estudio.

ABSTRACT Background: Immunotherapy consists of the administration of the allergen increasing doses to control sensitivity towards it. Objective: To describe the behavior of subcutaneous or sublingual immunotherapy to mites. Methodology: Retrospective study carried out in Cabaiguán, from 2010 to 2019, the universe of 267 patients with positive tests to mites and the sample 53 patients. Data were obtained from the data record. Results: 60.4 % used sublingual, the age group between 5-18 years prevailed (41.5 %), the subcutaneous was used in 39.6 %, and it was more frequent in males (58.5 %). The subcutaneous was indicated mainly in allergic rhinitis (20.7 %) and sublingual in asthma (32.1 %); for both, Dermatofagoide pteronyssinus was the highest sensitivity and use mite (43.4 %) the dominant administration time was 3 years (67.9 %). Symptom control was achieved by sublingual (37.7 %). In sublingual, there were no adverse events in 43.3 %, with the subcutaneous, 11.3 % of the adverse events were local and 7.6 % were mild systemic. Conclusions: Sublingual was the most used, the one with the highest control of symptoms and the fewest adverse events in the study.

Transition from clogging to continuous flow in constricted particle suspensions.

When suspended particles are pushed by liquid flow through a constricted channel, they might either pass the bottleneck without trouble or encounter a permanent clog that will stop them forever. However, they may also flow intermittently with great sensitivity to the neck-to-particle size ratio D/d. In this Rapid Communication, we experimentally explore the limits of the intermittent regime for a dense suspension through a single bottleneck as a function of this parameter. To this end, we make use of high time- and space-resolution experiments to obtain the distributions of arrest times (T) between successive bursts, which display power-law tails (∝T^{-α}) with characteristic exponents. These exponents compare well with the ones found for as disparate situations as the evacuation of pedestrians from a room, the entry of a flock of sheep into a shed, or the discharge of particles from a silo. Nevertheless, the intrinsic properties of our system (i.e., channel geometry, driving and interaction forces, particle size distribution) seem to introduce a sharp transition from a clogged state (α≤2) to a continuous flow, where clogs do not develop at all. This contrasts with the results obtained in other systems where intermittent flow, with power-law exponents above two, were obtained.

Sensibilización cutánea en pacientes alérgicos, utilizando extractos de ácaros Valergen / Skin sensitization in allergic patients, using Valergen mite extracts

RESUMEN Fundamento: Las enfermedades alérgicas constituyen un problema de salud mundial y los ácaros se encuentran entre sus principales agentes etiológicos. Objetivo: Describir el comportamiento de la sensibilización cutánea en pacientes alérgicos, utilizando extractos de ácaros Valergen. Metodología: Se realizó una investigación observacional transversal con 488 pacientes alérgicos de edades entre 5 y 55 años, de ambos sexos; a los cuales se les realizaron pruebas cutáneas con extractos alergénicos de ácaros en el período 2010-2017. Resultados: El 90.8 % de los pacientes mostró sensibilización cutánea positiva a los extractos utilizados, el 58.4 % fue del grupo de edades entre 5 y 14 años, el 51.2 % pertenecía al sexo femenino, predominaron los pacientes con rinitis y asma; la sensibilización cutánea en los pacientes con estas patologías alcanzó una positividad del 90.1 % y 90.6 % respectivamente; un 38.5 % de los pacientes tuvo como ácaro con mayor positividad al VALERGEN-DP (Dermatophagoides pteronyssinus). Conclusiones: Los extractos de ácaros VALERGEN-DP (Dermatophagoides pteronyssinus) de producción nacional, mostraron alta sensibilización cutánea en los pacientes alérgicos objeto de estudio; el ácaro de mayor positividad fue el VALERGEN-DP (Dermatophagoides pteronyssinus), seguido del VALERGEN-BT (Blomia tropicalis).

ABSTRACT Background: Allergic diseases are a global health problem and mites are among its main etiological agents. Objective: To describe the behavior of skin sensitization in allergic patients, using Valergen mite extracts. Methodology: A cross-sectional observational investigation was carried out with 488 allergic patients being 5 and 55 years old, from both sexes; which were made skin tests with allergenic extracts of mites in the period 2010-2017. Results: 90.8 % of the patients showed positive skin sensitization to the extracts used, 58.4 % were from between the 5 and 14 age group, 51.2 % were female, patients with rhinitis and asthma predominated; skin sensitization in patients with these pathologies reached a positivity of 90.1 % and 90.6 % respectively; 38.5 % of patients had a mite with greater positivity to VALERGEN-DP (Dermatophagoides pteronyssinus). Conclusions: Nationally produced extracts of VALERGEN-DP mites (Dermatophagoides pteronyssinus) showed high skin sensitization in the allergic patients under study; the most positive mite was VALERGEN-DP (Dermatophagoides pteronyssinus), followed by VALERGEN-BT (Blomia tropicalis).