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Abstract The CMS detector, including its muon system, has been operating at the CERN LHC in increasingly challenging conditions for about 15 years. The muon detector was designed to provide excellent triggering and track reconstruction for muons produced in proton–proton collisons at an instantaneous luminosity ( $$\mathcal {L}$$ L ) of $$1 \times 10^{34}$$ 1 × 10 34 cm $$^{-2}$$ - 2 s $$^{-1}$$ - 1 . During the Run 2 data-taking period (2015–2018), the LHC achieved an instantaneous luminosity of twice its design value, resulting in larger background rates and making the efficient detection of muons more difficult. While some backgrounds result from natural radioactivity, cosmic rays, and interactions of the circulating protons with residual gas in the beam pipe, the dominant source of background hits in the muon system arises from proton–proton interactions themselves. Charged hadrons leaving the calorimeters produce energy deposits in the muon chambers. In addition, high-energy particles interacting in the hadron calorimeter and forward shielding elements generate thermal neutrons, which leak out of the calorimeter and shielding structures, filling the CMS cavern. We describe the method used to measure the background rates in the various muon subsystems. These rates, in conjunction with simulations, can be used to estimate the expected backgrounds in the High-Luminosity LHC. This machine will run for at least 10 years starting in 2029 reaching an instantaneous luminosity of $$\mathcal {L} = 5 \times \text {10}^\text {34}\,\text {cm}^\text {-2}\,\text {s}^\text {-1}$$ L = 5 × 10 34 cm -2 s -1 and increasing ultimately to $$\mathcal {L} = 7.5 \times \text {10}^\text {34}\,\text {cm}^\text {-2}\,\text {s}^\text {-1}$$ L = 7.5 × 10 34 cm -2 s -1 . These background estimates have been a key ingredient for the planning and design of the muon detector upgrade.

Objectives. To determine the requirement and time to mechanical ventilation and Intensive Care Unit (ICU), hospitalization and hospitalization time, death and disability of the axonal variants of Guillain-Barré Syndrome (GBS) in comparison with the acute demyelinating variant in patients of all the ages. Materials and methods. The systematic review that included patients with GBS. The exposure variable was the axonal variants and the comparator was acute inflammatory demyelinating polyneuropathy (AIDP). The outcomes were the requirement and time on mechanical ventilation (MV), requirement and time in the ICU, hospitalization time, disability and death. The NewCasttle-Ottawa Scale (NOS) was used to assess risk of bias. A meta-analysis was conducted to calculate mean differences and relative risks (RR) with their 95% confidence intervals (CI) using inverse variances and random effects models. Results. Of the 3116 articles found, 46 met the selection criteria. The time on MV was 7.42 days (95% CI: 0.36 to 1.48) and the hospitalization time was 3.11 (95% CI: 0.73 to 5.49) days for the axonal variants. The axonal variants had a RR of 0.47 (95% CI: 0.24 to 0.92) for the requirement of MV in adults, but it was 1.68 (95% CI: 1.25 to 2.25) in children. There was a high statistical heterogeneity. Conclusions. Axonal variants showed, on average, longer MV and hospitalization time, overall and by subgroups. A high MV requirement was found for axonal variants in children; it was lower for adults.

El presente trabajo tiene como objetivo el estudio de la influencia de los cambios horarios en los turnos de trabajo sobre la salud, el descanso y el estrés percibido de las tripulaciones del Ejército del Aire Español desplegados en operaciones. Se seleccionó una muestra de 32 militares todos de sexo masculino y de edades comprendidas entre los 28 y los 53 años (M = 38.06; DT = 7.91) pertenecientes a una Unidad tipo Ala del Ejército del Aire. La evaluación se llevó a cabo en dos momentos, antes y durante la misión y tuvo en cuenta variables fisiológicas como la temperatura y el ritmo de actividad medidas por medio de sensores, así como una evaluación psicológica y subjetiva por medio de: la Escala de Matutinidad-Vespertinidad, el Índice de Calidad del sueño de Pittsburgh, la Escala de Somnolencia de Epworth y la Escala de Estrés Percibido. Los resultados mostraron como al perder regularidad periódica en los ciclos biológicos, los sujetos experimentan una menor calidad de su tiempo de descanso y los eventos se valoran como más estresantes. Se concluye que hay una tendencia a la pérdida de estabilidad y consistencia de los ritmos durante la misión: se debilitan y aparecen los problemas relacionados con el sueño.

El objetivo de esta investigación fue analizar la relación entre el funcionamiento familiar y el autoconcepto en adolescentes de una Unidad Educativa en la ciudad de Guaranda, Ecuador. En base a investigaciones previas y a observaciones preliminares en la institución, se ha considerado que la disfuncionalidad en el núcleo familiar limita las verdaderas potencialidades de los adolescentes. La metodología estuvo basada en el paradigma pospositivista, es cuantitativa, con alcance descriptivo y correlacional, no experimental de corte transversal. Se utilizaron el Cuestionario de Percepción del Funcionamiento Familiar y el Autoconcepto Forma 5, participaron 372 estudiantes de entre 15 a 19 años de segundo y tercero de bachillerato, con un 56,2 % mujeres y 43,8 % varones. Se obtuvieron puntuaciones moderadas, tanto en el funcionamiento familiar como en el autoconcepto. Se obtuvo una correlación positiva moderada (r=0,422; p: 0,01), por ende, se concluye que, a mayor funcionamiento familiar, mayor autoconcepto en los adolescentes.

Objetivo: El objetivo de éste estudio fue evaluar la intensidad de luz de las lámparas de fotocurado comercializadas en Guayaquil a un corto y mediano plazo, comparándolas con un valor inicial obtenido mediante la medición de la intensidad de luz de lámparas de fotocurado nuevas, además de determinar el porcentaje de lámparas de fotocurado utilizadas por odontólogos en Guayaquil que cumplen con el nivel de intensidad de luz mínimo (600 mW/cm2 ). Materiales y métodos: Se utilizó el radiómetro CURE RITE, EFOS, Mississagua, Ontario para medir la intensidad de lámparas de fotocurado nuevas, y se clasificaron por modelo y marca, se obtuvieron datos como costo y tipo de lámpara de fotocurado. Posteriormente, se visitó a odontólogos en consultorios y clínicas de la ciudad de Guayaquil y estudiantes en la Universidad Católica de Santiago de Guayaquil con el objetivo de medir la intensidad de las lámparas de fotocurado de las mismas marcas del control, después de un determinado tiempo de uso. Se formaron 3 grupos clasificados de acuerdo al costo: Grupo 1 ($1000 o más), Grupo 2 ($251 a $999), Grupo 3 (hasta $250). Se hizo una comparación entre los valores de control con los valores obtenidos para determinar el porcentaje de luz que se ha mantenido o perdido según el tiempo de uso. Además, se comparó el desempeño de los 3 grupos de lámparas de fotocurado. Resultados: En general, se observó que la intensidad de luz de las lámparas de fotocurado presentaba una tendencia a disminuir a medida que el tiempo de uso aumentaba. En el grupo 1, ninguna lámpara presentaba una intensidad menor a la mínima necesaria, mientras que en el grupo 2 y 3, un porcentaje del 24% y 23% no cumplía con el nivel de intensidad mínimo necesario respectivamente. Conclusiones: La intensidad de la luz de las lámparas de fotocurado tiende a disminuir con el tiempo de uso. La mayoría de lámparas de fotocurado estudiadas son aptas para realizar una correcta fotopolimerización.

Objectives: Patients with haematologic malignancies (HM) COVID-19 have more severe disease, with increased risk of mortality. Therefore, this study aimed to evaluate the effect of SARS-CoV-2 RNAemia and the specific humoral immune responses on the clinical outcomes of patients with HM and COVID-19. Methods: Interferon-α/γ (IFN-α/IFN-γ) serum levels, neutralizing antibodies and RNAemia at COVID-19 diagnosis, and persistent RNAemia during the follow-up were evaluated. Results: Overall, 63 (58.9%) out of 107 patients had RNAemia, which was persistent in 26 (41.3%) patients. RNAemia at diagnosis and persistent RNAemia were associated with the need for high-flow nasal oxygen therapy during admission. Persistent RNAemia, age >70 years, and CURB-65 score ≥2 in patients with pneumonia were associated with increased 90-day mortality (P = 0.009, P = 0.030 and P = 0.001, respectively). The 90-day overall survival was lower (P = 0.006) in patients with persistent RNAemia. In addition, dexamethasone administration was associated with a COVID-19 episode with persistent RNAemia. Conclusion: Our results suggest that in patients with HM, RNAemia at the time of COVID-19 diagnosis and during the follow-up can be used to stratify patients with HM according to their clinical evolution and to guide clinical decisions tailored to the specific needs of each patient.

Summary: Background: It is uncertain which biological features underpin the response of rectal cancer (RC) to radiotherapy. No biomarker is currently in clinical use to select patients for treatment modifications. Methods: We identified two cohorts of patients (total N = 249) with RC treated with neoadjuvant radiotherapy (45Gy/25) plus fluoropyrimidine. This discovery set included 57 cases with pathological complete response (pCR) to chemoradiotherapy (23%). Pre-treatment cancer biopsies were assessed using transcriptome-wide mRNA expression and targeted DNA sequencing for copy number and driver mutations. Biological candidate and machine learning (ML) approaches were used to identify predictors of pCR to radiotherapy independent of tumour stage. Findings were assessed in 107 cases from an independent validation set (GSE87211). Findings: Three gene expression sets showed significant independent associations with pCR: Fibroblast-TGFβ Response Signature (F-TBRS) with radioresistance; and cytotoxic lymphocyte (CL) expression signature and consensus molecular subtype CMS1 with radiosensitivity. These associations were replicated in the validation cohort. In parallel, a gradient boosting machine model comprising the expression of 33 genes generated in the discovery cohort showed high performance in GSE87211 with 90% sensitivity, 86% specificity. Biological and ML signatures indicated similar mechanisms underlying radiation response, and showed better AUC and p-values than published transcriptomic signatures of radiation response in RC. Interpretation: RCs responding completely to chemoradiotherapy (CRT) have biological characteristics of immune response and absence of immune inhibitory TGFβ signalling. These tumours may be identified with a potential biomarker based on a 33 gene expression signature. This could help select patients likely to respond to treatment with a primary radiotherapy approach as for anal cancer. Conversely, those with predicted radioresistance may be candidates for clinical trials evaluating addition of immune-oncology agents and stromal TGFβ signalling inhibition. Funding: The Stratification in Colorectal Cancer Consortium (S:CORT) was funded by the Medical Research Council and Cancer Research UK (MR/M016587/1).

Cardiac computed tomography (CCT) has assumed an increasingly significant role in the evaluation of coronary artery disease (CAD) during the past few decades, whereas cardiovascular magnetic resonance (CMR) remains the gold standard for myocardial tissue characterization. The discovery of late myocardial enhancement following intravenous contrast administration dates back to the 1970s with ex-vivo CT animal investigations; nevertheless, the clinical application of this phenomenon for cardiac tissue characterization became prevalent for CMR imaging far earlier than for CCT imaging.Recently the technical advances in CT scanners have made it possible to take advantage of late contrast enhancement (LCE) for tissue characterization in CCT exams. Moreover, the introduction of extracellular volume calculation (ECV) on cardiac CT images combined with the possibility of evaluating cardiac function in the same exam is making CCT imaging a multiparametric technique more and more similar to CMR.The aim of our review is to provide a comprehensive overview on the role of CCT with LCE in the evaluation of a wide range of cardiac conditions.

Immunoglobulin heavy chain variable (IGHV) region mutations, TP53 mutation, fluorescence in situ hybridization (FISH), and cytogenetic analysis are the most important prognostic biomarkers used in chronic lymphocytic leukemia (CLL) patients in our daily practice. In real-life environment, there are scarce studies that analyze the correlation of these factors with outcome, mainly referred to time to first treatment (TTFT) and overall survival (OS). This study aimed to typify IGHV mutation status, family usage, FISH aberrations, and complex karyotype (CK) and to analyze the prognostic impact in TTFT and OS in retrospective study of 375 CLL patients from a Spanish cohort. We found unmutated CLL (U-CLL) was associated with more aggressive disease, shorter TTFT (48 vs. 133 months, p

‘Redson’ is a new triploid, red-fleshed pomelo x grapefruit hybrid. The goal of this study was to examine the effects of rainfall, harvest time, tree age, and yield on the postharvest storage performance of ‘Redson’ fruit. During 2022/23, two postharvest storage trials were conducted with early- and late-harvested fruit. The fruit from the early harvest retained good quality for up to 16 weeks of storage at 7.5 °C plus 1 week at 22 °C, whereas the late-harvested fruit suffered from a high decay incidence. During 2023/24, we expanded the postharvest trials to nine different fruit sets harvested from early season (late October) until the end of the season (January). Fruit quality was examined under the same storage conditions after 6 and 16 weeks, and the results indicated that early- and mid-season fruit retained good quality with minimal decay incidence even after prolonged storage for 16 weeks, whereas the late-season fruit suffered from significant decay incidences of 17–22% and a decline in flavor acceptability. Further analysis revealed strong and significant correlations between various rainfall parameters and harvest time and decay incidences. Overall, early-harvested fruit during the autumn had a superior postharvest storage performance, whereas late-harvested fruit during the rainy winter suffered from decay development.

Cotija and Bola de Ocosingo are artisanal ripened cheeses produced in Mexico. Both are made with raw bovine milk from free-grazing cows and with no starter cultures. Unlike culture-based techniques, molecular methods for pathogen detection in food allow a shorter turnaround time, higher detection specificity, and represent a lower microbiological risk for the analyst. In the present investigation, we analyzed 111 cheese samples (95 Cotija and 16 Bola de Ocosingo) by qPCR (TaqMan®) after an enrichment-culture step specific to each foodborne bacterium. The results showed that 100% of the samples were free of DNA from Listeria monocytogenes, Brucella spp., Escherichia coli enterotoxigenic (ETEC), and O157:H7; 9% amplified Salmonella spp. DNA; and 11.7%, Staphylococcus aureus DNA. However, the threshold cycle (Ct) values of the amplified targets ranged between 23 and 30, indicating DNA from non-viable microorganisms. Plate counts supported this assumption. In conclusion, 100% of the cheeses analyzed were safe to consume, and the enrichment step before DNA extraction proved essential to discern between viable and non-viable microorganisms. Hygienic milking, milk handling, cheese manufacturing, and ripening are crucial to achieve an adequate microbiological quality of cheeses made with raw milk.

This research explores the use of the pepN activity fluorescent sensor DCM-Ala in bacterial biofilms, emphasizing its significance due to the critical role of biofilms in various biological processes. Advanced imaging techniques were employed to visualize pepN activity, introducing a novel approach to examining biofilm maturity. We found that the overexpression of pepN increases the ability of E. coli to form biofilm. The findings demonstrate varying levels of pepN activity throughout biofilm development, suggesting potential applications in biofilm research and management. The results indicate that the fluorescent emission from this sensor could serve as a reliable indicator of biofilm maturity, and the imaging techniques developed could enhance our understanding and control of biofilm-related processes. This work highlights the importance of innovative methods in biofilm study and opens new avenues for utilizing chemical emissions in biofilm management.

Abstract Aromatase inhibitors (AIs) reduce recurrences and mortality in postmenopausal patients with oestrogen receptor positive (ER+) breast cancer (BC), but >20% of patients will eventually relapse. Given the limited understanding of intrinsic resistance in these tumours, here we conduct a large-scale molecular analysis to identify features that impact on the response of ER + HER2- BC to AI. We compare the 15% of poorest responders (PRs, n = 177) as measured by proportional Ki67 changes after 2 weeks of neoadjuvant AI to good responders (GRs, n = 190) selected from the top 50% responders in the POETIC trial and matched for baseline Ki67 categories. In this work, low ESR1 levels are associated with poor response, high proliferation, high expression of growth factor pathways and non-luminal subtypes. PRs having high ESR1 expression have similar proportions of luminal subtypes to GRs but lower plasma estradiol levels, lower expression of estrogen response genes, higher levels of tumor infiltrating lymphocytes and immune markers, and more TP53 mutations.

Los páramos son ecosistemas conocidos por su gran capacidad de retención hídrica y secuestro de carbono en los suelos, esto se atribuye a la variedad de flora y fauna de las zonas de humedales en los mismos. La presente investigación se realizó en el Páramo de Sayaro, ubicado en la parroquia de Juan Montalvo, perteneciente a el cantón Cayambe; con el objetivo de determinar la cantidad de carbono que se encuentra presente en tres zonas con distintos niveles de intervención y cuáles serían los factores a los que se atribuiría la diferencia. Zona Z1=sin intervención; Zona Z2=mediana intervención y Zona Z3= alta intervención. Se tomaron un total de 45 muestras de suelo, 15 en cada una de las zonas, para análisis fisicoquímicos del porcentaje de materia orgánica y la cantidad de carbono orgánico; determinados mediante el método de Walkey y Black (1947). Los valores promedios obtenidos de carbono orgánico fueron de 44,06 tC/ha en la zona sin intervención y de paramos jóvenes; 28,05 tC/ha en la zona con mediana intervención por la presencia de ceniza volcánica y 35,67 tC/ha en la zona con alta intervención por la vegetación y presencia de organismos como las lombrices.

Abstract Introduction Logically valid deductive arguments are clear examples of abstract recursive computational procedures on propositions or on probabilities. However, it is not known if the cortical time-consuming inferential processes in which logical arguments are eventually realized in the brain are in fact physically different from other kinds of inferential processes. Methods In order to determine whether an electrical EEG discernible pattern of logical deduction exists or not, a new experimental paradigm is proposed contrasting logically valid and invalid inferences with exactly the same content (same premises and same relational variables) and distinct logical complexity (propositional truth-functional operators). Electroencephalographic signals from 19 subjects (24.2 ± 3.3 years) were acquired in a two-condition paradigm (100 trials for each condition). After the initial general analysis, a trial-by-trial approach in beta-2 band allowed to uncover not only evoked but also phase asynchronous activity between trials. Results showed that (i) deductive inferences with the same content evoked the same response pattern in logically valid and invalid conditions, (ii) mean response time in logically valid inferences is 61.54% higher, (iii) logically valid inferences are subjected to an early (400 ms) and a late reprocessing (600 ms) verified by two distinct beta-2 activations (p-value

Cryptorchidism in males constitutes a notable risk factor for both infertility and testicular cancer. Infertility in adulthood is closely linked to the germ cell status in childhood. Furthermore, the significance of germ cell status is important as more than 95% of all reported testicular malignancies are germ cell tumors. The review aims to elucidate the pathogenesis of germ cells in cryptorchid testes concerning their association with infertility and testicular malignancies. Impaired germ cell numbers are evident in cryptorchid testes even during antenatal and neonatal stages. In cryptorchidism there is a rapid decline in germ cell number within the first year of life, partially attributed to physiologic gonocyte apoptosis. Additionally, germ cells fail to differentiate normally during mini-puberty leading to reduced germ cell proliferation and delayed clearance of gonocytes from the seminiferous epithelium. Absence of germ cells in testicular biopsies occurs already 10 months of age and germ cell deterioration progressively worsens with approximately 50% of persisting cryptorchid testes lacking germ cells during puberty. The deficient germ cell maturation and proliferation leads to later infertility. Elevated temperature in the cryptorchid testes and also hormonal deficiency contribute to this phenomenon. Germ cell neoplasia in situ (GCNIS) originating during fetal development may manifest in rare cases associated with disorders of sexual development, chromosomal abnormalities in boys, specific syndromes, and teratomas that include cryptorchidism. In adults, the presence of GCNIS predominantly represents a new histology pattern before invasive germ cell cancer is demonstrated and is neither congenital nor related to abnormal gonocyte transformation.

Introducción: Dentro del contexto de la pandemia de COVID-19, los niños se quedaron confinados en sus hogares. La región del Área Metropolitana de Buenos Aires (AMBA) concentra la mayor densidad urbana de la Argentina y ha sido el epicentro de contagios y muertes por COVID-19. Los objetivos del presente estudio son caracterizar los hábitos del uso de pantalla, de sedentarismo y de la actividad física y describir sus asociaciones, en niños menores a seis años, del AMBA, Argentina. Métodos: estudio analítico y transversal, en que se utilizaron los datos de la encuesta en línea (Google Forms®). Mediante un muestreo no probabilístico por conveniencia, se invitaron a participar padres, madres, tutores legales y cuidadores de niños/as menores de seis años. La encuesta estuvo disponible durante cuatro meses del periodo de cuarentena y estuvo conformada por 32 preguntas sobre uso de pantalla, actividad física y sedentarismo de los niños. Resultados: fueron respondidas 256 encuestas, la mayoría (79,6%) era del género femenino y 50,8% en el rango etario de 31-40 años. Conclusión: La televisión es la más utilizada y los niños empiezan a usar pantallas táctiles a partir de un año. El tiempo de juego de los adultos con los niños y el tiempo que ellos suelen realizar actividades como leer un libro o dibujar es de una a dos horas por día. Hubo asociación entre ser dueño de la pantalla y usarla por más horas. Cuanto menor el nivel de ingreso, más tiempo los adultos juegan con sus niños.

Background and Aims: The observed increase in the incidence of early-onset colorectal cancer (EOCRC) is being driven by sporadic cases, but the molecular characteristics of these tumors are not fully understood. Our objective was to investigate the prevalence of microsatellite instability (MSI) and selected mutations in sporadic EOCRC, and their association with survival. Methods: Firstly, we compared the prevalence of molecular characteristics and survival within a population-based cohort study of 652 stage II and III colon cancer patients in Northern Ireland, comparing sporadic early-onset (

We propose that an information technology and computational framework that would unify access to hospital digital information silos, and enable integration of this information using machine learning methods, would bring a new paradigm to patient management and research. This is the core principle of Integrated Diagnostics (ID): the amalgamation of multiple analytical modalities, with evolved information technology, applied to a defined patient cohort, and resulting in a synergistic effect in the clinical value of the individual diagnostic tools. This has the potential to transform the practice of personalized oncology at a time at which it is very much needed.In this article we present different models from the literature that contribute to the vision of ID and we provide published exemplars of ID tools. We briefly describe ongoing efforts within a universal healthcare system to create national clinical datasets. Following this, we argue the case to create “hospital units” to leverage this multi-modal analysis, data integration and holistic clinical decision-making. Finally, we describe the joint model created in our institutions.

IntroductionGranulosa cells (GCs) and theca cells (TCs) play a pivotal role in human ovarian steroidogenesis, facilitating the conversion of cholesterol into sex steroids that regulate normal reproductive function. This study aims to explore the expression patterns of key enzymes that govern human ovarian steroidogenesis throughout follicle development, employing both genomic and immunological methodologies. MethodsFollicles and GCs obtained from women undergoing ovarian tissue cryopreservation (OTC) and in vitro fertilisation treatment were utilized. Gene expression data were obtained from a Chinese study using RNA sequencing and from microarray data generated in our laboratory to comprehensively analyse gene expression profiles across distinct stages of follicular development. To corroborate the localisation of key enzymes within GCs and TCs, immunohistochemistry analyses utilizing colourimetric and fluorescent techniques were conducted.ResultsSteroidogenesis-related enzymes displayed low gene expression levels during early follicle development. However, a notable upregulation of HSD3B2 was observed in GCs as follicles progressed to the antral/preovulatory stage, confirmed consistently using both microarray and RNA sequencing methodologies. Furthermore, immunohistochemical analyses effectively demonstrated that HSD3B2 were not only expressed in GCs, but co-localised with CYP17A1 within a specific subset of TCs surrounding human small antral follicles. Contributing to an enhanced progesterone production during the second half of the follicular phase was a significant upregulation of CYB5A in both microarray and RNA-seq datasets as follicles transition from the antral stage to the pre-ovulatory stage. Moreover, an augmented expression of DHCR24 and LDLR in both types of data, along with HMGCR expression expression in the microarray data, indicates increased substrate availability for ovarian steroidogenesis.DiscussionThis study confirms and extends that GCs gradually augment expression of HSD3B2 thereby enhancing their capacity for progesterone synthesis as follicles reach the size of selection at around 10 mm in diameter. This is supported by the expression CYB5A and possibly augmented availability of steroid precursors. A subset of TCs exhibit concurrent expression of CYP17A1 and HSD3B2, collectively contributing to the synthesis of 17-hydroxyprogesterone. These data significantly enhance our understanding of the dynamic regulation of progesterone throughout the process of follicular development.

Abstract Background The suggested effects of the oocyte secreted GDF9 and BMP15 growth factors on oocyte maturation are currently based on recombinant proteins, and little is known about native GDF9 and BMP15 in humans. Methods Human immature cumulus-oocyte complexes (COCs) obtained in connection with ovarian tissue cryopreservation (OTC) underwent in vitro maturation (IVM). Oocyte-produced GDF9 and BMP15 were detected in COCs using immunofluorescence, and in fresh GV oocytes and in GV and MII oocytes after IVM by western blot. Concentrations of GDF9, BMP15 homodimers, and GDF9/BMP15 heterodimer in spent media after IVM were measured by ELISA. The relative expression of seven genes from the GDF9 and BMP15 signaling pathways (BMPR2, ALK5, ALK6, SMAD1, SMAD2, SMAD3, and SMAD5) was evaluated in fresh cumulus cells (before IVM) and in cumulus cells from GV and MII oocytes after IVM by RT-qPCR. Results We detected native pro-mature GDF9 and BMP15 in human oocytes with molecular weights (Mw) of 47 kDa and 43 kDa, respectively. Concentrations of GDF9 and BMP15 in spent media after IVM were detected in 99% and 64% of the samples, respectively. The GDF9/BMP15 heterodimer was detected in 76% of the samples. Overall, the concentration of GDF9 was approximately 10-times higher than BMP15. The concentrations of both GDF9 and BMP15 were significantly lower in spent medium from MII oocytes than in media from oocytes that remained at the GV stage. Concentrations of the GDF9/BMP15 heterodimer did not differ between GV and MII oocytes. Furthermore, BMPR2, SMAD3, and SMAD5 were significantly upregulated in cumulus cells from MII oocytes, indicating that both GDF9 and BMP15 signaling were active during oocyte meiotic resumption in vitro. Conclusion These data suggest that the driving mechanisms for oocyte nuclear maturation may involve both GDF9 and BMP15 homodimers, while the role of the GDF9/BMP15 heterodimer is questionable.

Water is becoming an essential commodity for human life and is one of the most important natural resources. Public water utilities provide more than 90 percent of the world's water supply today, so a safe water distribution system is critical for any city. The importance, huge capital cost of the system, and growing city size lead to water distribution network optimization. In this work, we propose and compare two algorithms to optimize the water network design of a new neighborhood of our city, where a public cooperative is in charge of this utility. Consequently, two metaheuristic algorithms based on Tabu Search and Simulated Annealing (SOTS and HSA, respectively) arise to minimize the investment cost of a water distribution network. The experimentation suggests that both algorithms optimize the investment cost, with results that are comparable.

ˆCCL24 is a pro-fibrotic, pro-inflammatory chemokine expressed in several chronic fibrotic diseases. In the liver, CCL24 plays a role in fibrosis and inflammation, and blocking CCL24 led to reduced liver injury in experimental models. We studied the role of CCL24 in primary sclerosing cholangitis (PSC) and evaluated the potential therapeutic effect of blocking CCL24 in this disease. Multidrug resistance gene 2–knockout (Mdr2–/–) mice demonstrated CCL24 expression in liver macrophages and were used as a relevant experimental PSC model. CCL24-neutralizing monoclonal antibody, CM-101, significantly improved inflammation, fibrosis, and cholestasis-related markers in the biliary area. Moreover, using spatial transcriptomics, we observed reduced proliferation and senescence of cholangiocytes following CCL24 neutralization. Next, we demonstrated that CCL24 expression was elevated under pro-fibrotic conditions in primary human cholangiocytes and macrophages, and it induced proliferation of primary human hepatic stellate cells and cholangiocytes, which was attenuated following CCL24 inhibition. Correspondingly, CCL24 was found to be highly expressed in liver biopsies of patients with PSC. CCL24 serum levels correlated with Enhanced Liver Fibrosis score, most notably in patients with high alkaline phosphatase levels. These results suggest that blocking CCL24 may have a therapeutic effect in patients with PSC by reducing liver inflammation, fibrosis, and cholestasis.

Intro: Methicillin susceptibility prevails within clinically relevant Staphylococcus aureus strains. This study aimed to describe proportions of Methicillin- Susceptible S. aureus (MSSA), prescription behavior for its treatment, and impact of a post-prescription antimicrobial stewardship (AMS) strategy within two private tertiary care Mexican hospitals over 10 years. Methods: Patients older than 14 years with an S. aureus culture-proven infection between 2011 to 2020 were included. Disease was classified as monomicrobial or polymicrobial; strains were classified as MSSA if Cefoxitin susceptible. Spectrum Score was calculated according to the participants’ antibiotic regimen at: admission, 72 hours after culture results, and end-of- therapy. During the last two years analyzed, post-prescription review with feedback to prescribers as an AMS strategy. MSSA rates were compared within both time periods. Findings: We identified 1322 clinically relevant S. aureus strains isolated from 2011 to 2020. A total of 817 specimens were MSSA (61.8%), while only 505 demonstrated methicillin resistance(38.2%). During the antimicrobial stewardship period, MSSA proportion increased by 21.6% compared to the pre- intervention period(78.9% vs 57.3%). In patients with monomicrobial MSSA infections, mean decrease Spectrum Score was lower at end of therapy in comparison to that calculated 72 hours after culture results(1.3 vs 0.2 points). The latter didn't seem to differ when contrasting the Spectrum score between the period before(0.3 points) and after(0.2 points) the AMS intervention. The three most commonly used antimicrobials at admission, 72 hours after culture results, and end of therapy were respectively: Ceftriaxone, Meropenem, Vancomycin; Clindamycin, Vancomycin, Linezolid; and Trimethoprim/Sulfamethoxazole, Clindamycin, Ciprofloxacin. Conclusion: MSSA caused more infections in comparison to methicillin-resistant strains in our studied population. Despite the poor antimicrobial de-escalation in MSSA infections, evidenced by the high Spectrum scores, methicillin resistance has decreased over time. Post prescription interventions have not proven to be effective at these private hospitals and AMS strategies should be expanded to continue avoiding antibiotic resistance.

Abstract Colorectal carcinoma is one of the most common types of malignancy and a leading cause of cancer‐related death. Although clinicopathological parameters provide invaluable prognostic information, the accuracy of prognosis can be improved by using molecular biomarker signatures. Using a large dataset of immunohistochemistry‐based biomarkers (n = 66), this study has developed an effective methodology for identifying optimal biomarker combinations as a prognostic tool. Biomarkers were screened and assigned to related subsets before being analysed using an iterative algorithm customised for evaluating combinatorial interactions between biomarkers based on their combined statistical power. A signature consisting of six biomarkers was identified as the best combination in terms of prognostic power. The combination of biomarkers (STAT1, UCP1, p‐cofilin, LIMK2, FOXP3, and ICOS) was significantly associated with overall survival when computed as a linear variable (χ2 = 53.183, p

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Background: Undernutrition impairs linear growth while restoration of nutritional provisions leads to accelerated growth patterns. However, the composition of the nutrition provided is key to facilitating effective catch-up growth without compromising bone quantity, quality, and long-term health. Methods: We evaluated the role of a whey protein concentrate enriched in bovine milk exosomes (BMEs) in modulating the proliferative properties of human chondrocytes in vitro and studied how these effects might impact bone quantity and quality measured as longitudinal tibia growth, bone mineral content (BMC) and density (BMD), and trabecular micro-CT parameters in stunted rats during catch-up growth. Results: BMEs promoted proliferation in C28/I2 human chondrocytes mediated by mTOR-Akt signaling. In a stunting rat model, two-week supplementation with BMEs during refeeding was associated with improved tibia BMD, trabecular microstructure (trabecular number (Tb. N.) and space (Tb. Sp.)), and a more active growth plate (higher volume, surface, and thickness) compared to non-supplemented stunted rats. Positive effects on physis translated to significantly longer tibias without compromising bone quality when extending the refeeding period for another two weeks. Conclusions: Overall, BME supplementation positively contributed to longitudinal bone growth and improved bone quantity and quality during catch-up growth. These findings might be relevant for improving diets aimed at addressing the nutritional needs of children undergoing undernutrition during early life. [ABSTRACT FROM AUTHOR]