Longitudinal profiling of human androgenotes through single-cell analysis unveils paternal gene expression dynamics in early embryo development.

STUDY QUESTION: How do transcriptomics vary in haploid human androgenote embryos at single cell level in the first four cell cycles of embryo development? SUMMARY ANSWER: Gene expression peaks at the fourth cell cycle, however some androcytes exhibit unique transcriptional behaviors. WHAT IS KNOWN ALREADY: The developmental potential of an embryo is determined by the competence of the oocyte and the sperm. However, studies of the contribution of the paternal genome using pure haploid androgenotes are very scarce. STUDY DESIGN, SIZE, DURATION: This study was performed analyzing the single-cell transcriptomic sequencing of 38 androcytes obtained from 10 androgenote bioconstructs previously produced in vitro (de Castro et al., 2023). These results were analyzed through different bioinformatics software such as g: Profiler, GSEA, Cytoscape, and Reactome. PARTICIPANTS/MATERIALS, SETTING, METHODS: Single cell sequencing was used to obtain the transcriptomic profiles of the different androcytes. The results obtained were compared between the different cycles studied using the DESeq2 program and functional enrichment pathways using g: Profiler, Cytoscape, and Reactome. MAIN RESULTS AND THE ROLE OF CHANCE: A wave of paternally driven transcriptomic activation was found during the third-cell cycle, with 1128 upregulated and 225 downregulated genes and the fourth-cell cycle, with 1373 upregulated and 286 downregulated genes, compared to first-cell cycle androcytes. Differentially expressed routes related to cell differentiation, DNA-binding transcription, RNA biosynthesis and RNA polymerase II transcription regulatory complex, and cell death were found in the third and fourth with respect to the first-cell cycle. Conversely, in the fourth cell cycle, 153 downregulated and 332 upregulated genes were found compared with third cell cycle, associated with differentially expressed processes related to E-box binding and zinc finger protein 652 (ZNF652) transcription factor. Further, significant overexpression of LEUTX, PRAMEF1, DUXA, RFPL4A, TRIM43, and ZNF675 found in androgenotes, compared to biparental embryos, highlights the paternal contributions to zygote genome activation. LARGE SCALE DATA: All raw sequencing data are available through the Gene Expression Omnibus (GEO) under accessions number: GSE216501. LIMITATIONS, REASONS FOR CAUTION: Extrapolation of biological events from uniparental constructs to biparental embryos should be done with caution. Maternal and paternal genomes do not act independently of each other in a natural condition. The absence of one genome may affect gene transcription of the other. In this sense, the haploid condition of the bioconstructs could mask the transcriptomic patterns of the single cells. WIDER IMPLICATIONS OF THE FINDINGS: The results obtained demonstrated the level of involvement of the human paternal haploid genome in the early stages of embryo development as well as its evolution at the transcriptomic level, laying the groundwork for the use of these bioconstructs as reliable models to dispel doubts about the genetic role played by the paternal genome in the early cycles of embryo development. STUDY FUNDING/COMPETING INTEREST(S): This study was funded by Instituto de Salud Carlos III (ISCIII) through the project 'PI22/00924', co-funded by European Regional Development Fund (ERDF); 'A way to make Europe'. F.D. was supported by the Spanish Ministry of Economy and Competitiveness through the Miguel Servet program (CPII018/00002). M.J.E. was supported by Instituto de Salud Carlos III (PI19/00577 [M.J.E.]) and FI20/00086. P.dC. was supported by a predoctoral grant for training in research into health (PFIS PI19/00577) from the Instituto de Salud Carlos III. All authors declare having no conflict of interest with regard to this trial.

Insulin eye drops for refractory corneal epithelial defects. A case series / Colirio de insulina para defectos corneales epiteliales persistentes. Una serie de casos

Objetive: To report the clinical course of a case series of patients with persistent epithelial corneal defects (PECD) treated with insulin eye drops. Method: Retrospective review of five patients -four non-diabetic and one diabetic- in treatment with insulin eye drops 1 U/mL four times a day (QID). Results: Patients developed refractory epithelial ulcers due to different etiology (three infections, one trauma and one chemical injury). After treatment with topical insulin all defects were healed in about 30-60 days. Conclusion: Insulin formulated as 1 U/mL eye drops and administered QID can be an effective and safe option for PECD. (AU)

Objetivo: Comunicar la evolución clínica de una serie de casos de pacientes con defectos corneales epiteliales persistentes (PECD) tratados con colirio de insulina. Método: Revisión retrospectiva de cinco pacientes –cuatro no diabéticos y uno diabético– en tratamiento con colirio de insulina 1 U/mL cuatro veces al día (QID). Resultados: Los pacientes desarrollaron úlceras epiteliales refractarias de diferente etiología (tres infecciones, un traumatismo y una lesión química). Tras el tratamiento con insulina tópica todos las lesiones se curaron en unos 30-60 días. Conclusión: La insulina formulada en forma de colirio de 1 U/mL y administrada QID puede ser una opción eficaz y segura para la PECD. (AU)

Mosaic results after preimplantation genetic testing for aneuploidy may be accompanied by changes in global gene expression.

Aneuploidy in preimplantation embryos is a major cause of human reproductive failure. Unlike uniformly aneuploid embryos, embryos diagnosed as diploid-aneuploid mosaics after preimplantation genetic testing for aneuploidy (PGT-A) can develop into healthy infants. However, the reason why these embryos achieve full reproductive competence needs further research. Current RNA sequencing techniques allow for the investigation of the human preimplantation transcriptome, providing new insights into the molecular mechanisms of embryo development. In this prospective study, using euploid embryo gene expression as a control, we compared the transcriptome profiles of inner cell mass and trophectoderm samples from blastocysts with different levels of chromosomal mosaicism. A total of 25 samples were analyzed from 14 blastocysts with previous PGT-A diagnosis, including five low-level mosaic embryos and four high-level mosaic embryos. Global gene expression profiles visualized in cluster heatmaps were correlated with the original PGT-A diagnosis. In addition, gene expression distance based on the number of differentially expressed genes increased with the mosaic level, compared to euploid controls. Pathways involving apoptosis, mitosis, protein degradation, metabolism, and mitochondrial energy production were among the most deregulated within mosaic embryos. Retrospective analysis of the duration of blastomere cell cycles in mosaic embryos revealed several mitotic delays compared to euploid controls, providing additional evidence of the mosaic status. Overall, these findings suggest that embryos with mosaic results are not simply a misdiagnosis by-product, but may also have a genuine molecular identity that is compatible with their reproductive potential.

Tb3+-Tb3+ cross-relaxation study under novel experimental technique: Simultaneous laser excitation at UV-Vis.

Tb3+ doped GeO2-Na2O glasses have been fabricated by conventional melt quenching technique using 0.3, 1, 3, and 5 %mol of terbium ions. The optical properties were studied by means of steady-state photoluminescence (excitation and emission spectra), and emission decay time. Under excitation of 355 nm and as the concentration of dopant increases, the glasses show an enhancement of the emission intensity from 5D4 level accompanied by a decrease on the emission intensity from 5D3 level. This phenomenon can be attributed to an energy transfer process that occurs through cross-relaxation mechanisms between Tb3+ ions. The aim of this study is to report an experimental technique to study the cross-relaxation of 5D3 level decay curves of Tb3+ ions under simultaneous temporal and spatial pulsed excitation using UV and visible light (355 nm + 488 nm), allowing to limit the occurrence of cross-relaxation mechanisms and increase luminescent efficiency. Upon simultaneous UV + Vis excitation, the emission from 5D3 level in enhanced, as the energy of the 488 nm pulse is increased. Additionally, the energy transfer efficiency between Tb3+ ions was analyzed with the Inokuti-Hirayama (IH) model, as function of the excitation pulse energy at 488 nm, keeping fixed the energy of the 355 nm pulse, determining a dipole-dipole interaction as the dominant interaction mechanism.

Recomendaciones para el empleo de técnicas neurofisiológicas en el diagnóstico de muerte encefálica de la Sociedad de Neurofisiología Clínica de las Comunidades de Valencia y Murcia / Recommendations for the use of neurophysiological techniques in the diagnosis of brain death from the Clinical Neurophysiology Society of the Communities of Valencia and Murcia

En España, el trasplante de órganos constituye uno de los mayores retos y trabajo en equipo de los centros hospitalarios. Se estima que en 2020 España aportó a la Unión Europea el 19% de la totalidad de los donantes. El diagnóstico de apoyo confirmatorio recomienda por ley algunas técnicas complementarias en determinados casos, entre ellas las técnicas neurofisiológicas, en especial el uso del electroencefalograma y los potenciales evocados. Estos casos plantean al neurofisiólogo clínico la toma acertada de decisiones tanto clínicas como técnicas para su correcta realización e interpretación. Hasta ahora no existe a nivel nacional un consenso de realización de estas técnicas. Es una revisión bibliográfica actualizada sobre las técnicas neurofisiológicas (electroencefalograma y potenciales evocados), con análisis mediante método Delphi y juicio de expertos del grupo de trabajo de la Sociedad de Neurofisiología Clínica de las Comunidades de Valencia y Murcia. Las técnicas neurofisiológicas permiten ser un apoyo en el diagnóstico de muerte encefálica, tanto de forma confirmatoria como para acortar tiempos de observación. Para su realización se precisan unos mínimos estándares técnicos que permitan realizar de forma óptima los estudios. Especialmente hay que tener en cuenta la medicación, la situación hemodinámica, la ausencia de hipotermia y el grupo de edad. Presentamos la primera guía en castellano elaborada por la Sociedad de Neurofisiología de las Comunidades de Valencia y Murcia para la realización en nuestros hospitales de las técnicas neurofisiológicas en el diagnóstico de muerte encefálica.(AU)

In Spain organ transplantation constitutes one of the greatest challenges and teamwork of hospital centres. It is estimated that in the year 2020 Spain contributed 19% of all donors to the European Union. The confirmatory support diagnosis recommends by law some complementary techniques in certain cases, including neurophysiological techniques, especially the use of electroencephalogram and evoked potentials. These cases require the clinical neurophysiologist to make the right clinical and technical decisions for the correct performance and interpretation of the same. To date, there is no national consensus on the performance of these techniques. Updated bibliographic review on neurophysiological techniques (electroencephalogram and evoked potentials). Analysis by Delphi method and expert judgment of the working group of the Clinical Neurophysiology Society of the Communities of Valencia and Murcia. Neurophysiological techniques can be a support in the diagnosis of encephalic death, both confirmatory and to shorten observation times. In order to perform them, minimum technical standards are required to allow optimal performance of the studies, especially taking into account medication, hemodynamic situation, absence of hypothermia, and age group. We present the first guide in Spanish elaborated by the Society of Neurophysiology of the Communities of Valencia and Murcia for the performance in our hospitals of neurophysiological techniques in the diagnosis of brain death.(AU)

Miocarditis y miocardiopatía inflamatoria confirmadas por biopsia endomiocárdica: perfil clínico y pronóstico / Endomyocardial biopsy-confirmed myocarditis and inflammatory cardiomyopathy: clinical profile and prognosis

Introducción y objetivos La biopsia endomiocárdica (BEM) es la única técnica capaz de establecer el diagnóstico etiológico de pacientes con miocarditis o miocardiopatía inflamatoria (MI). El objetivo de este estudio es conocer el perfil clínico, la evolución y los factores pronósticos de los pacientes con sospecha de miocarditis o MI sometidos a BEM. Métodos Se analizaron retrospectivamente las características clínicas, los hallazgos histológicos y la evolución de todos los pacientes con sospecha de miocarditis o MI sometidos a BEM entre 1997 y 2019 en un hospital terciario español. Se evaluó el rendimiento del diagnóstico histológico mediante los criterios de Dallas frente a los criterios inmunohistoquímicos (IHQ). Resultados Se realizó BEM a 99 pacientes (el 67% varones; edad, 42± 15 años; fracción de eyección media, 34±14%). El 28% presentaba miocarditis o MI confirmada por criterios de Dallas y el 54% aplicando los criterios IHQ (p <0,1). Se diagnosticaron 47 miocarditis linfocitarias, 6 miocarditis eosinofílicas, 3 sarcoidosis y 1 miocarditis de células gigantes. Tras una mediana de seguimiento de 18 meses, 23 pacientes (23%) precisaron trasplante cardiaco o asistencia ventricular o fallecieron. El 21% de los pacientes con miocarditis confirmada mediante IHQ precisó trasplante cardiaco o asistencia o falleció, frente al 7% de aquellos sin inflamación (p=0,056). La fracción de eyección ≤ 30%, un diámetro telediastólico del ventrículo izquierdo ≥60mm y una clase NYHA III-IV iniciales se asociaron con peor pronóstico, especialmente en presencia de inflamación. Conclusiones La BEM permite establecer un diagnóstico etiológico en más de la mitad de los casos de sospecha de miocarditis o MI cuando se emplean técnicas IHQ. La inflamación confirmada por IHQ añade valor pronóstico y permite identificar a los pacientes con mayor probabilidad de sufrir complicaciones (AU)

Introduction and objectives Endomyocardial biopsy (EMB) is the only technique able to establish an etiological diagnosis of myocarditis or inflammatory cardiomyopathy (ICM). The aim of this study was to analyze the clinical profile, outcomes, and prognostic factors of patients with suspected myocarditis/ICM undergoing EMB. Methods We retrospectively analyzed the clinical characteristics, histological findings, and follow-up data of all patients with suspected myocarditis or ICM who underwent EMB between 1997 and 2019 in a Spanish tertiary hospital. The diagnostic yield was compared using the Dallas criteria vs immunohistochemical criteria (IHC). Results A total of 99 patients underwent EMB (67% male; mean age, 42±15 years; mean left ventricular ejection fraction [LVEF], 34%±14%). Myocarditis or ICM was confirmed in 28% with application of the Dallas criteria and in 54% with the IHC criteria (P <.01). Lymphocytic myocarditis was diagnosed in 47 patients, eosinophilic myocarditis in 6, sarcoidosis in 3, and giant cell myocarditis in 1 patient. After a median follow-up of 18 months, 23 patients (23%) required heart transplant (HTx), a left ventricular assist device (LVAD), and/or died. Among the patients with IHC-confirmed myocarditis, 21% required HTx/LVAD or died vs 7% of those without inflammation (P=.056). The factors associated with a worse prognosis were baseline LVEF ≤ 30%, left ventricular end-diastolic diameter ≥ 60mm, and NYHA III-IV, especially in the presence of inflammation. Conclusions EMB allows an etiological diagnosis in more than half of patients with suspected myocarditis/ICM when IHC techniques are used. IHC-confirmed inflammation adds prognostic value and helps to identify patients with a higher probability of developing complications (AU)

A frequency comb stabilized Ti:Sa laser as a self-reference for ion-trap experiments with a 40Ca+ ion.

In this study, we report on the stabilization of a continuous-wave Ti:Sa laser to an optical frequency comb. The laser is emitting at 866 nm to address one of the transitions required for Doppler cooling of a single 40Ca+ ion in a linear Paul trap (2D3/2 ↔P1/22). The stabilized Ti:Sa laser is utilized to calibrate an ultra-accurate wavelength meter. We certify this self-reference laser source by comparing the results from monitoring the laser-cooled 40Ca+ ion in the linear Paul trap, with those obtained when a HeNe laser is used for calibration. The use of this self-reference is compatible with the simultaneous use of the comb for precision spectroscopy in the same ion-trap experiment.

[Recommendations for the use of neurophysiological techniques in the diagnosis of brain death from the Clinical Neurophysiology Society of the Communities of Valencia and Murcia]. / Recomendaciones para el empleo de técnicas neurofisiológicas en el diagnóstico de muerte encefálica de la Sociedad de Neurofisiología Clínica de las Comunidades de Valencia y Murcia.

In Spain organ transplantation constitutes one of the greatest challenges and teamwork of hospital centres. It is estimated that in the year 2020 Spain contributed 19% of all donors to the European Union. The confirmatory support diagnosis recommends by law some complementary techniques in certain cases, including neurophysiological techniques, especially the use of electroencephalogram and evoked potentials. These cases require the clinical neurophysiologist to make the right clinical and technical decisions for the correct performance and interpretation of the same. To date, there is no national consensus on the performance of these techniques. Updated bibliographic review on neurophysiological techniques (electroencephalogram and evoked potentials). Analysis by Delphi method and expert judgment of the working group of the Clinical Neurophysiology Society of the Communities of Valencia and Murcia. Neurophysiological techniques can be a support in the diagnosis of encephalic death, both confirmatory and to shorten observation times. In order to perform them, minimum technical standards are required to allow optimal performance of the studies, especially taking into account medication, hemodynamic situation, absence of hypothermia, and age group. We present the first guide in Spanish elaborated by the Society of Neurophysiology of the Communities of Valencia and Murcia for the performance in our hospitals of neurophysiological techniques in the diagnosis of brain death.

TITLE: Recomendaciones para el empleo de técnicas neurofisiológicas en el diagnóstico de muerte encefálica de la Sociedad de Neurofisiología Clínica de las Comunidades de Valencia y Murcia.En España, el trasplante de órganos constituye uno de los mayores retos y trabajo en equipo de los centros hospitalarios. Se estima que en 2020 España aportó a la Unión Europea el 19% de la totalidad de los donantes. El diagnóstico de apoyo confirmatorio recomienda por ley algunas técnicas complementarias en determinados casos, entre ellas las técnicas neurofisiológicas, en especial el uso del electroencefalograma y los potenciales evocados. Estos casos plantean al neurofisiólogo clínico la toma acertada de decisiones tanto clínicas como técnicas para su correcta realización e interpretación. Hasta ahora no existe a nivel nacional un consenso de realización de estas técnicas. Es una revisión bibliográfica actualizada sobre las técnicas neurofisiológicas (electroencefalograma y potenciales evocados), con análisis mediante método Delphi y juicio de expertos del grupo de trabajo de la Sociedad de Neurofisiología Clínica de las Comunidades de Valencia y Murcia. Las técnicas neurofisiológicas permiten ser un apoyo en el diagnóstico de muerte encefálica, tanto de forma confirmatoria como para acortar tiempos de observación. Para su realización se precisan unos mínimos estándares técnicos que permitan realizar de forma óptima los estudios. Especialmente hay que tener en cuenta la medicación, la situación hemodinámica, la ausencia de hipotermia y el grupo de edad. Presentamos la primera guía en castellano elaborada por la Sociedad de Neurofisiología de las Comunidades de Valencia y Murcia para la realización en nuestros hospitales de las técnicas neurofisiológicas en el diagnóstico de muerte encefálica.

Effective lifting of the topological protection of quantum spin Hall edge states by edge coupling.

The scientific interest in two-dimensional topological insulators (2D TIs) is currently shifting from a more fundamental perspective to the exploration and design of novel functionalities. Key concepts for the use of 2D TIs in spintronics are based on the topological protection and spin-momentum locking of their helical edge states. In this study we present experimental evidence that topological protection can be (partially) lifted by pairwise coupling of 2D TI edges in close proximity. Using direct wave function mapping via scanning tunneling microscopy/spectroscopy (STM/STS) we compare isolated and coupled topological edges in the 2D TI bismuthene. The latter situation is realized by natural lattice line defects and reveals distinct quasi-particle interference (QPI) patterns, identified as electronic Fabry-Pérot resonator modes. In contrast, free edges show no sign of any single-particle backscattering. These results pave the way for novel device concepts based on active control of topological protection through inter-edge hybridization for, e.g., electronic Fabry-Pérot interferometry.

ADENI-UCI study: Analysis of non-income decisions in ICU as a measure of limitation of life support treatments.

OBJECTIVE: To analyze the variables associated with ICU refusal decisions as a life support treatment limitation measure. DESIGN: Prospective, multicentrico. SCOPE: 62 ICU from Spain between February 2018 and March 2019. PATIENTS: Over 18 years of age who were denied entry into ICU as a life support treatment limitation measure. INTERVENTIONS: None. MAIN INTEREST VARIABLES: Patient comorities, functional situation as measured by the KNAUS and Karnosfky scale; predicted scales of Lee and Charlson; severity of the sick person measured by the APACHE II and SOFA scales, which justifies the decision-making, a person to whom the information is transmitted; date of discharge or in-hospital death, destination for hospital discharge. RESULTS: A total of 2312 non-income decisions were recorded as an LTSV measure of which 2284 were analyzed. The main reason for consultation was respiratory failure (1080 [47.29%]). The poor estimated quality of life of the sick (1417 [62.04%]), the presence of a severe chronic disease (1367 [59.85%]) and the prior functional limitation of patients (1270 [55.60%]) were the main reasons for denying admission. The in-hospital mortality rate was 60.33%. The futility of treatment was found as a risk factor associated with mortality (OR: 3.23; IC95%: 2.62-3.99). CONCLUSIONS: Decisions to limit ICU entry as an LTSV measure are based on the same reasons as decisions made within the ICU. The futility valued by the intensivist is adequately related to the final result of death.

Site-specific recognition of SARS-CoV-2 nsp1 protein with a tailored titanium dioxide nanoparticle.

The ongoing world-wide Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2) pandemic shows the need for new sensing and therapeutic means against the CoV viruses. The SARS-CoV-2 nsp1 protein is important, both for replication and pathogenesis, making it an attractive target for intervention. In recent years nanoparticles have been shown to interact with peptides, ranging in size from single amino acids up to proteins. These nanoparticles can be tailor-made with specific functions and properties including bioavailability. To the best of our knowledge, in this study we show for the first time that a tailored titanium oxide nanoparticle interacts specifically with a unique site of the full-length SARS-CoV-2 nsp1 protein. This can be developed potentially into a tool for selective control of viral protein functions.

[An unusual cause of a decline in general health in a very old person]. / Une cause inhabituelle d'altération de l'état général chez une personne très âgée.

Humans are accidental intermediate hosts and a dead-end for the echinococcosis parasite. No cases of hydatid echinococcosis (hydatid cyst) have ever been described in a French-born very elderly person, who has never been out of France. We report the case of a 90-year-old man hospitalised following a decline in his general health and the discovery of a liver mass on the CT-scan. The abdominal palpation was painless, and no mass was felt. Biological tests revealed hypereosinophilia, a mild inflammatory syndrome, a slight increase in the immunoglobulin E level, and positive serology for Echinococcus granulosus. A diagnosis of hydatid echinococcosis due to Echinococcus granulosus was made given the liver mass on the CT-scan, the positive serology and the hypereosinophilia. Management consisted of watch and wait. This observation is interesting because it was a case of an autochthonous hydatid cyst of an unexpected discovery in a very elderly patient. Indeed, even though the discovery was classical, the clinical presentation was singular because of the context.

L'être humain est un hôte intermédiaire accidentel et une impasse parasitaire pour l'échinococcose. Aucun cas de kyste hydatique (échinococcose hydatique) n'a été décrit chez une personne très âgée née en France et ne l'ayant jamais quittée. Nous rapportons ici le cas d'un patient âgé de 90 ans hospitalisé pour altération de l'état général et découverte d'une masse hépatique à la tomodensitométrie. La palpation abdominale était indolore sans masse perçue. Le bilan biologique révélait une hyperéosinophilie, un discret syndrome inflammatoire, une légère augmentation du taux d'immunoglobuline E et une sérologie de l'Echinococcus granulosus positive. Le diagnostic d'échinococcose hydatique (kyste hydatique) due à Echinococcus granulosus fut alors posé, compte tenu de la masse hépatique découverte à la tomodensitométrie, de la sérologie positive et de l'hyperéosinophilie. La prise en charge a consisté en une attitude «watch and wait¼. Cette observation est intéressante car il s'agissait d'un cas de kyste hydatique autochtone de découverte fortuite chez un patient très âgé. En effet, même si le mode de découverte était classique, le tableau clinique était singulier en raison du contexte.

Drug-drug interactions between treatment specific pharmacotherapy and concomitant medication in patients with COVID-19 in the first wave in Spain.

Primary aim was to assess prevalence and severity of potential and real drug-drug interactions (DDIs) among therapies for COVID-19 and concomitant medications in hospitalized patients with confirmed SARS-CoV-2 infection. The secondary aim was to analyze factors associated with rDDIs. An observational single center cohort study conducted at a tertiary hospital in Spain from March 1st to April 30th. rDDIs refer to interaction with concomitant drugs prescribed during hospital stay whereas potential DDIs (pDDIs) refer to those with domiciliary medication. DDIs checked with The University of Liverpool resource. Concomitant medications were categorized according to the Anatomical Therapeutic Chemical classification system. Binomial logistic regression was carried out to identify factors associated with rDDIs. A total of 174 patients were analyzed. DDIs were detected in 152 patients (87.4%) with a total of 417 rDDIs between COVID19-related drugs and involved hospital concomitant medication (60 different drugs) while pDDIs were detected in 105 patients (72.9%) with a total of 553 pDDIs. From all 417 rDDIs, 43.2% (n = 180) were associated with lopinavir/ritonavir and 52.9% (n = 221) with hydroxychloroquine, both of them the most prescribed (106 and 165 patients, respectively). The main mechanism of interaction observed was QTc prolongation. Clinically relevant rDDIs were identified among 81.1% (n = 338) ('potential interactions') and 14.6% (n = 61) (contraindicated) of the patients. Charlson index (OR 1.34, 95% IC 1.02-1.76) and number of drugs prescribed during admission (OR 1.42, 95% IC 1.12-1.81) were independently associated with rDDIs. Prevalence of patients with real and pDDIs was high, especially those clinically relevant. Both comorbidities and polypharmacy were found as risk factors independently associated with DDIs development.

Aharonov-Bohm Oscillations in Minimally Twisted Bilayer Graphene.

We investigate transport in the network of valley Hall states that emerges in minimally twisted bilayer graphene under interlayer bias. To this aim, we construct a scattering theory that captures the network physics. In the absence of forward scattering, symmetries constrain the network model to a single parameter that interpolates between one-dimensional chiral zigzag modes and pseudo-Landau levels. Moreover, we show how the coupling of zigzag modes affects magnetotransport. In particular, we find that scattering between parallel zigzag channels gives rise to Aharonov-Bohm oscillations that are robust against temperature, while coupling between zigzag modes propagating in different directions leads to Shubnikov-de Haas oscillations that are smeared out at finite temperature.

Copper and lead exposures disturb reproductive features of primary endometrial stromal and epithelial cells.

This study investigates if Cu and Pb act as endocrine disruptors affecting endometrial cells. Primary EnSCs and EnECs were exposed to Cu (0, 50, 100 and 200 µM) or Pb (0, 30, 100 and 500 µM) and assessed for viability, decidualization, apoptosis and proliferation on EnSCs, and wound healing and adhesion capabilities on EnECs. Cu exposure decreased significantly cell viability in a dose-dependent manner. Cu and Pb negatively affected in vitro decidualization, showing a significant decrease in PRL secretion. HOXA10 and ERα mRNA levels significantly decreased in decidualized cells (dEnSCs) exposed to Cu. Cu and Pb decreased adhesion and regeneration capability in EnEC. This study reveals that Cu and Pb could negatively affect endometrial functionality, compromising the decidualization process and disrupting endometrial regeneration and embryo adhesion. Therefore, special care should be taken considering heavy metals exposure if pregnancy is being pursued.

ADENI-UCI Study: Analysis of non-income decisions in ICU as a measure of limitation of life support treatments. / Estudio ADENI-UCI: Análisis de las decisiones de no ingreso en UCI como medida de limitación de los tratamientos de soporte vital.

OBJECTIVE: To analyze the variables associated with ICU refusal decisions as a life support treatment limitation measure. DESIGN: Prospective, multicentrico SCOPE: 62 ICU from Spain between February 2018 and March 2019. PATIENTS: Over 18 years of age who were denied entry into ICU as a life support treatment limitation measure. INTERVENTIONS: None. MAIN INTEREST VARIABLES: Patient comorities, functional situation as measured by the KNAUS and Karnosfky scale; predicted scales of Lee and Charlson; severity of the sick person measured by the APACHE II and SOFA scales, which justifies the decision-making, a person to whom the information is transmitted; date of discharge or in-hospital death, destination for hospital discharge. RESULTS: A total of 2312 non-income decisions were recorded as an LTSV measure of which 2284 were analyzed. The main reason for consultation was respiratory failure (1080 [47.29%]). The poor estimated quality of life of the sick (1417 [62.04%]), the presence of a severe chronic disease (1367 [59.85%]) and the prior functional limitation of patients (1270 [55.60%]) were the main reasons for denying admission. The in-hospital mortality rate was 60.33%. The futility of treatment was found as a risk factor associated with mortality (OR: 3.23; IC95%: 2.62-3.99). CONCLUSIONS: Decisions to limit ICU entry as an LTSV measure are based on the same reasons as decisions made within the ICU. The futility valued by the intensivist is adequately related to the final result of death.

Efectos de la curva de aprendizaje en los resultados de la duodenopancreatectomía cefálica en un hospital de nivel II / Effects of the learning curve on the results of cephalic pancreaticoduodenectomy in a level II hospital

Resumen Introducción: La duodeno pancreatectomía cefálica es una operación compleja cuyos resultados a corto plazo son multifactoriales. Objetivo: Evaluar el impacto de la curva de aprendizaje en los resultados a corto plazo de la duodenopancreatectomía cefálica en un hospital de nivel II. Materiales y Método: Se analizaron los datos obtenidos a partir de una base de datos mantenida prospectivamente desde 2005. Se definieron dos periodos de tiempo: de 2005 a 2011 y de 2012 a 2017. Se compararon la morbilidad, mortalidad y estancia postoperatoria de ambos períodos. Resultados: Durante el período de tiempo estudiado se hicieron 126 duodenopancreatectomías cefálicas, 61 durante la primera etapa y 65 durante la segunda. La tasa de transfusión intraoperatoria se redujo de 33% a 15% (p = 0,011). La tasa de transfusión postoperatoria se redujo de 39 a 23% (p = 0,021). No hubo diferencias significativas con respecto a la incidencia global de complicaciones postoperatorias (59% y 52,3%). La incidencia de abscesos intraabdominales fue significativamente menor en el segundo período (18% y 4,6%, respectivamente; p = 0,038). La tasa de reintervenciones se redujo significativamente, de 22% a 9% (p = 0,049). También se redujo significativamente la tasa de mortalidad, de 6,56% a 0% (p = 0,032). La estancia media postoperatoria disminuyó significativamente en el segundo período, pasando de 19,6 a 15,8 días (p = 0,001), con una mayor proporción de pacientes dados de alta en los 8 primeros días de postoperatorio (11,5% y 38,5%, respectivamente; p = 0,001). Conclusión: La curva de aprendizaje es un factor que permite mejorar los resultados de la duodenopancreatectomía cefálica, en un hospital de nivel II, hasta alcanzar valores similares a los de un hospital de nivel III.

Introduction: The duodenum pancreatectomy cephalic is a complex operation whose short-term results are multifactorial. Aim: To assess the impact of the learning curve on the short-term outcomes of cephalic duodenopancreatectomy at a level II hospital. Materials Method: We analyze the data obtained from a database maintained prospectively since 2005. Two time periods were defined: from 2005 to 2011 and from 2012 to 2017. The morbidity, mortality and postoperative stay of both periods were compared. Results: 126 cephalic duodenopancreatectomies were performed, 61 during the first period and 65 during the second. The intraoperative transfusion rate was reduced from 33% to 15% (p = 0.011). The postoperative transfusion rate was reduced from 39 to 23% (p = 0.021). There were no significant differences with respect to the overall incidence of postoperative complications (59% and 52.3%, respectively). However, the incidence of intra-abdominal abscesses was significantly lower in the second period (18% and 4.6%, respectively, p = 0.038). The rate of reoperations was significantly reduced, from 22% to 9% (p = 0.049). The mortality rate was also significantly reduced, from 6.56% to 0% (p = 0.032). The mean postoperative stay decreased significantly in the second period, from 19.6 to 15.8 days (p = 0.001), with a higher proportion of patients discharged in the first 8 postoperative days (11.5% and 38.5%, respectively, p = 0.001). Conclusion: The learning curve is a factor allows improving the results of cephalic pancreaticoduodenectomy, in a level II hospital, until reaching values similar to those of a level III hospital.

Inhibition of KIF20A by BKS0349 reduces endometriotic lesions in a xenograft mouse model.

Several studies have suggested a possible etiological association between ovarian endometriosis and ovarian cancer. Evidence has shown that KIF20A overexpression might confer a malignant phenotype to ovarian tumors by promoting proliferation and inhibiting apoptosis. However, no data about the role of KIF20A in endometriosis have been described. In this study, the human endometrium (n = 4) was transfected by mCherry adenovirus and intraperitoneally implanted in mice. Subsequently, mice were divided in three groups (n = 8/group) that were treated with Vehicle, BKS0349 (KIF20A-antagonist) or cabergoline (dopamine receptor agonist) for 21 days. mCherry-labeled endometriotic lesions were monitored over time using the IVIS Imaging System. Mice were sacrificed 72 h after the last administration; proliferation was evaluated by immunohistochemistry and apoptosis by TUNEL. CCND1 gene expression (G1 phase-related gene) was measured by qRT-PCR. A significant reduction in mCherry-fluorescent signal was observed in the BKS0349 group after treatment ended (D24) compared with D0 (P-value = 0.0313). Moreover, the mCherry signal on D24 showed a significant decrease in the BKS0349 group compared with controls (P-value = 0.0303), along with significant size reduction of endometriotic lesions observed in the BKS0349 group compared with control on D24 (P-value = 0.0006). Functional studies showed a significant reduction in proliferating cells in the BKS0349-treated group compared with controls (P-value = 0.0082). In addition, CCND1 expression was decreased in the BKS0349 group compared with control (P-value = 0.049) at D24 and a significant increase in apoptotic cells among endometriotic lesions in BKS0349-treated mice was observed compared with control (P-value = 0.0317). Based on these findings, we concluded that BKS0349 induces apoptosis and inhibits cell proliferation, reducing endometriotic lesion size and suggesting KIF20A inhibition by BKS0349 as a novel therapeutic treatment for endometriosis.